Small volume oral transmucosal dosage forms containing sufentanil for treatment of pain

ABSTRACT

Compositions, systems and methods for administration of small volume sufentanil drug dosage forms to the sublingual mucosa of a subject for treatment of pain using a device are disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. patent application Ser. No.14/517,260, filed Oct. 17, 2014, which is a Continuation of U.S. patentapplication Ser. No. 11/985,162, filed Nov. 14 , 2007, which issued asU.S. Pat. No. 8,865,743, which is a Continuation-In-Part of U.S. patentapplication Ser. No. 11/650,174, filed. Jan. 5, 2007, which issued asU.S. Pat. No. 8,202,535, which claims the priority benefit to U.S.Provisional Application No. 60/756,937, filed Jan. 6, 2006, each ofwhich is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The invention relates to drug dispensing devices and systems for oraltransmucosal administration of small volume drug dosage forms to asubject, wherein the drug dosage forms comprise sufentanil for treatmentof pain.

BACKGROUND OF THE INVENTION

Oral dosage forms account for approximately eighty percent of all thedrug dosage forms on the market. They are non-invasive, easilyadministered and have high patient compliance. Orally administeredtherapeutic agents, however, must be transported to the stomach andsmall intestine for absorption across the gastrointestinal (GI) mucosalmembranes into the blood. The efficiency of absorption of a drugfollowing oral administration can be low because of metabolism withinthe GI tract and first-pass metabolism within the liver, resulting inrelatively lengthy onset times or erratic absorption characteristicsthat are not well-suited to control acute disorders. The majority oforal dosage forms on the market are designed for GI delivery. Relativelyfew oral dosage forms are designed for delivery through the oral mucosa.

Oral transmucosal delivery offers a number of advantages in that it canprovide a shorter onset time to maximal plasma concentration (C_(max))than oral delivery, in particular for lipophilic drugs. This is becausethe drug rapidly passes directly and efficiently through the epitheliumof the highly vascularized mucosal tissue to the plasma, thus rapidlyreaching the circulation while avoiding slower, often inefficient andvariable GI uptake. It is therefore advantageous for a drug to bedelivered through the mucous membranes of the oral cavity, (e.g., viathe sublingual route), when rapid onset, consistent T_(max) and C_(max)are advantageous.

In the process of oral transmucosal drug delivery, the drug is absorbedthrough the epithelial membranes of the oral cavity. However, frequentlythe key risk associated with oral transmucosal delivery is the enhancedpotential for swallowing the medication owing to the continuousgeneration, backward flow and swallowing of the saliva. This becomes aparticular risk when the dosage forms employed are large enough toproduce a significant saliva response, which, in turn, leads toswallowing of drug and/or loss of adherence of the dosage form to theoral mucosa.

Various solid dosage forms, such as sublingual tablets, troches,lozenges, lozenges-on-a-stick, chewing gums, and buccal patches havebeen used to deliver drugs via the oral mucosal tissue. Solid dosageforms such as lozenges and tablets have been used for oral transmucosaldelivery of drugs such as nitroglycerin sublingual tablets.

Reproducible and effective drug delivery technology represents an areaof active research, in particular, as it applies to controlledsubstances such as opioids like sufentanil.

The relevant art does not describe a solid drug dosage form for deliveryof sufentanil to the oral mucosa, such as the sublingual space.

Controlled access oral transmucosal drug dispensing systems offernumerous advantages over conventional means of drug administration suchas oral and intravenous routes, the most important of which is enhancedsafety, with additional advantages being rapid and consistent onset ofaction, more consistent and predictable plasma concentrations and higherand more consistent bioavailability than currently available dosageforms.

This is particularly relevant to the treatment of pain, morespecifically, acute (i.e. post-operative), intermittent and breakthroughpain.

Therefore, a need exists for drug dosage forms, methods and systems foradministration of an opioid, such as sufentanil (e.g., bypatient-controlled administration), for treatment of pain, wherein thedrug dosage form is administered with a device which provides for safeand controlled delivery of the drug via the oral mucosa, whileminimizing the potential for drug abuse and/or diversion.

The present invention addresses these needs.

BRIEF SUMMARY OF THE INVENTION

Disclosed herein are dosage forms for sublingual administration ofsufentanil to a subject wherein the dosage forms comprise from about 5to about 100 micrograms (mcg) of sufentanil, and a bioadhesive material,wherein the bioadhesive material provides for adherence to thesublingual mucosa of the subject.

Typically, the dosage forms have a volume of less than 30 microliters ora mass of less than 30 mg.

Erosion of the disclosed dosage forms is complete in from about 6minutes to about 25 minutes following sublingual administration to asubject and the dosage forms are effective to deliver at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 98% or at least 99% ofthe total amount of sufentanil in the dosage form via the sublingualroute.

A single sublingual administration of the disclosed sufentanil dosageforms to a subject results in one or more of the following: abioavailability of greater than 50%; an AUC_(inf) with a coefficient ofvariation of less than 40%; a T_(max) with a coefficient of variation ofless than 40%; a linear relationship between C_(max) and the amount ofsufentanil in the dosage form; and a linear relationship betweenAUC_(inf) and the amount of sufentanil in the dosage form.

Repeated sublingual administrations of the disclosed sufentanil dosageforms to a subject results in one or more of the following: abioavailability which is greater than the bioavailability following asingle sublingual administration to the subject; a difference betweenthe T_(max) following repeated sublingual administration and the time ofthe previous sublingual administration which is shorter than the T_(max)following a single sublingual administration to the subject; and aT_(max) with a coefficient of variation of less than 40%.

The disclosed sufentanil dosage forms find utility in methods fortreating pain, wherein a handheld dispensing device is used forplacement of a sufentanil dosage form in the sublingual space of asubject. Placement/administration may be patient controlled.

The disclosed handheld dispensing devices comprise one or more of thefollowing features: a housing having a dispensing end with a means toprevent or retard saliva ingress; a lock-out feature; a patientidentification feature; and a disposable cartridge configured to holdone or more drug dosage forms. The lock-out feature may provide forrepeated sublingual administration of sufentanil at a minimum intervalof 20 minutes.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graphic depiction of sufentanil plasma concentrationmean+/−standard deviation (SD) versus time, following sublingualadministration of 2.5, 5, 10 and 20 mcg (5 mcg every 10 minutes×4 doses)sufentanil dosage forms (slow-eroding) in healthy human volunteers.

FIG. 2 is a graphic depiction of the linearity of C_(max) (mean+/−SD)versus sufentanil dose (mcg), following sublingual administration of2.5, 5, 10 or 4×5 mcg sufentanil dosage forms (slow-eroding) in healthyhuman volunteers.

FIG. 3 is a graphic depiction of the linearity of AUC_(inf) (mean+/−SD)versus sufentanil dose (mcg), following sublingual administration of2.5, 5, 10 or 4×5 mcg sufentanil dosage forms (slow-eroding) in healthyhuman volunteers.

FIG. 4 is a graphic depiction of sufentanil plasma concentration(mean+/−SD) versus time, following repeated sublingual administration offour 5 mcg sufentanil dosage forms (slow-eroding) at 10 minute intervalsin healthy human volunteers as compared to IV Infusion of 5 mcgsufentanil over 10 minutes.

FIGS. 5A and 5B provide a graphic depiction of observed and predictedsufentanil plasma concentration (mean+/−SD) versus time, followingrepeated sublingual administration of 4×5 mcg sufentanil dosage forms(slow-eroding) at 10 minute intervals in healthy human volunteers over aperiod of 12 hours (FIG. 5A) or a period of 2.5 hours (FIG. 5B).

FIG. 6 is a graphic depiction of sufentanil plasma concentrations(mean+/−SD) versus time, following sublingual administration of 10, 40(10 mcg every 20 minutes×4 doses) and 80 mcg sufentanil dosage forms(faster-eroding) in healthy human volunteers.

FIGS. 7A and 7B are a graphic depiction of observed and predictedsufentanil plasma concentration (mean+/−SD) versus time, followingrepeated sublingual administration of 4×10 mcg sufentanil dosage forms(faster-eroding) at 20 minute intervals in healthy human volunteers overa period of 12 hours (FIG. 7A) or a period of 2.5 hours (FIG. 7B).

FIG. 8 is a graphic depiction of the linearity of C_(max) (mean+/−SD)versus sufentanil dose (mcg), following sublingual administration of 10,4×10 or 80 mcg sufentanil dosage forms (faster-eroding) in healthy humanvolunteers.

FIG. 9 is a graphic depiction of the linearity of AUC_(inf) (mean+/−SD)versus sufentanil dose (mcg), following sublingual administration of 10,4×10 or 80 mcg sufentanil dosage forms (faster-eroding) in healthy humanvolunteers.

FIGS. 10A and 10B provide a graphic depiction of steady-state sufentanilplasma concentration versus time predicted by superposition followingrepeated sublingual administration of 10 mcg doses of sufentanil at 20minute intervals (FIG. 10A) or 15 mcg doses of sufentanil at 20 minuteintervals (FIG. 10B).

FIGS. 11A-E provide a schematic depiction of an exemplary dispensingdevice wherein the device is designed to deliver drug dosage forms tooral mucosa of a patient under treatment. FIGS. 11A-E illustrate theprogression of Intact drug dispensing device 11 (FIG. 11A); the reusablehead 13 and disposable body 15 of a drug dispensing device (FIG. 11B); areusable head 13, disposable body 15 and cartridge 17, a dispense button23, and a proboscis 31 of a drug dispensing device (FIG. 11C); variousaspects of a drug dispensing device 11 including a reusable head 13,disposable body 15 and cartridge 17, a proboscis 31, and a latch 19 tounlock the device, a hub lock 21, a distal seal 33, 35, and a powertrain coupling 25 (FIG. 11D); and a reassembled intact drug dispensingdevice 11 (FIG. 11E).

FIG. 12 is a schematic depiction of an exemplary dispensing deviceshowing features designed to block or retard saliva and moistureingress. The preferred embodiment includes a dispensing tip having ashroud 29, having one or more of: a wiping seal/valve 33, 35, anabsorbent pad 39, a pushrod 51, a drying chamber/moisture communicationchannel 43, desiccant in the channel 45, a cartridge 17 containingdosage forms 67 and desiccant in the cartridge 47.

FIGS. 13A and 13B are schematic depictions of an exemplary geometry fora dispensing tip.

FIGS. 14A-D are a schematic depiction of an exemplary proboscis 31 of adispensing device 11 wherein the proboscis 31 has an S-shape 53 andcomprises a shroud 29 and a valve. The shroud shields the valve frommoisture and saliva ingress from the tongue and other mucosa andprovides an area for the dosage form to exit the device without“sticking” to the wetted distal valve or shroud area. The shroud alsocomprises a cut-out/relief 55 in order to mitigate the dragging ofdosage forms when the device is removed from the oral space. The valvefunctions with the shroud to control saliva and moisture ingress, aswell as aid in delivery of the dosage form.

FIGS. 15A-D provide a series of flow diagrams for use of an exemplarydevice showing the stages of push rod/tablet interaction during deviceuse, wherein FIG. 15A shows the LOAD feature; FIG. 15B shows theCALIBRATE feature; FIG. 15C shows the DISPENSE feature; and FIG. 15Dshows the DISASSEMBLE feature.

FIG. 16 is a schematic depiction of an exemplary device showing thestages of push rod/tablet interaction during device use. In FIG. 16, thepush rod 51, dosage forms 67, shipping tablet 69, spring 73 and positionsensor 71 are shown. During use, the push rod 51 moves between positions57, 59, 61, 63, 65 and 67, also shown in FIG. 16.

FIG. 17 is a schematic architecture connection diagram illustrating thevarious components that may be included in a drug dispensing device orsystem including a device with a separate drug dispensing device head13, drug dispensing device body 15, drug cartridge 17, a portabledocking FOB 113, a patient RFID tag 115, and a base station 117.

FIG. 18A is a block diagram illustrating one aspect of communication inthe drug dispensing system, including an RFID tag, a drug dispensingdevice, a base station/dock and a healthcare provider personal computer.

FIG. 18B is a block diagram illustrating another aspect of communicationin a drug dispensing system, including an RFID tag, a drug dispensingdevice, a portable docking FOB, a base station and a healthcare providerpersonal computer.

DETAILED DESCRIPTION OF THE INVENTION

I. Introduction

Provided herein are compositions, methods, systems and kits forsublingual administration of sufentanil-containing small volume dosageforms using a device. Sublingual administration of the dosage formsminimizes the saliva response and therefore minimizes delivery of thedrug to the GI tract, such that the majority of drug is delivered acrossthe oral mucosa. The small volume dosage forms have bioadhesiveproperties which facilitate adherence to the oral mucosa, thusminimizing the risk of ingestion and Inefficient delivery due toswallowing.

The claimed small volume sufentanil-containing dosage forms which arealso called “Sublingual Sufentanil NanoTabs™” offer a number ofadvantages in terms of both safety and efficacy as compared to currentlyavailable pain treatments.

The following disclosure provides a description of the dosage forms,devices, methods, systems and kits which constitute the invention. Theinvention is not limited to the specific dosage forms, devices,methodology, systems, kits or medical conditions described herein, assuch may, of course, vary. It is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “and”, and “the” include plural references unlessthe context clearly dictates otherwise. Thus, for example, reference to“a drug formulation” includes a plurality of such formulations andreference to “a drug delivery device” includes systems comprising drugdosage forms and devices for containment, storage and delivery of suchdosage forms.

Unless defined otherwise, all technical and scientific terms used hereingenerally have the same meaning as commonly understood to one ofordinary skill in the art to which this invention belongs. Although anymethods, devices and materials similar or equivalent to those describedherein can be used in the practice or testing of the invention, thepreferred methods, devices and materials are now described.

All publications mentioned herein are incorporated herein by referencein their entirety for the purpose of describing and disclosing thecompositions and methodologies which are described in the publicationswhich might be used in connection with the presently describedinvention. The publications discussed herein are provided solely fortheir disclosure prior to the filing date of the present application.Nothing herein is to be construed as an admission that the invention isnot entitled to antedate such a disclosure by virtue of prior invention.

II. Definitions

The term “active agent” or “active” may be used interchangeably hereinwith the term “drug” and Is meant to refer to any therapeutically activeagent.

The term “adhere” is used herein with reference to a drug dosage form orformulation that is in contact with a surface such as a mucosal surfaceand is retained on the surface without the application of an externalforce. The term “adhere” is not meant to imply any particular degree ofsticking or bonding, nor is it meant to imply any degree of permanency.

The term “analgesic drug” as used herein includes sufentanil or asufentanil congener, such as alfentanil, fentanyl, lofentanil,carfentanil, remifentanil, trefentanil, or mirfentanil, as well asformulations comprising one or more therapeutic compounds. Use of thephrase “sufentanil or a congener” is not meant to be limiting to use of,or formulations comprising, only one of these selected opioid compounds.Furthermore, reference to sufentanil alone or to a selected sufentanilcongener alone, e.g., reference to “alfentanil”, is understood to beonly exemplary of the drugs suitable for delivery according to themethods of the invention, and is not meant to be limiting in any way.

The term “AUC” as used herein means “area under the curve”, and is alsoreferred to as “AUC_(inf)” in a plot of concentration of drug in plasmaversus time. AUC is typically given for the time interval zero toinfinity, however, dearly plasma drug concentrations cannot be measured‘to infinity’ for a patient so a mathematical equation is used toestimate the AUC from a limited number of concentration measurements.AUC_(inf)=AUC_(t) +C _(last)/λ_(z) where C _(last) was the last plasmaconcentration.

In a practical sense, AUC_(inf) represents the total amount of drugabsorbed by the body, irrespective of the rate of absorption. This isuseful when trying to determine whether two formulations of the samedose release the same dose of drug to the body. The AUC_(inf) of atransmucosal dosage form compared to that of the same dosageadministered intravenously serves as the basis for a measurement ofbioavailability.

The term “bioadhesion” as used herein refers to adhesion to a biologicalsurface including mucosal membranes.

The term “bioavailability” or “F” as used herein means “percentbioavailability” and represents the fraction of drug absorbed from atest article as compared to the same drug when administeredintravenously. It is calculated from the AUC_(inf) of the test articlefollowing delivery via the intended route versus the AUC_(inf) for thesame drug after intravenous administration. The absolute bioavailabilityof sublingual administration was determined by the following formula:

${F(\%)} = {\frac{{AUC}_{\inf}^{sublingual}}{{AUC}_{\inf}^{IV}} \times \frac{{Dose}_{IV}}{{Dose}_{sublingual}}}$

The term “breakthrough pain” as used herein, is a transitory flare ofpain of moderate to severe intensity occurring on a background ofotherwise controlled pain. “Breakthrough pain” can be intense for shortperiods of time, as short as 1 or 2 minutes or as long as 30 minutes ormore.

The term “cartridge” is used herein with reference to a disposablecartridge configured to hold one or more drug dosage forms, typically,one up to 200 drug dosage forms. The cartridge typically comprises asmart cartridge recognition system with a physical keyed feature on thecartridge, a bar code on the cartridge, a magnetic tag on the cartridge,an RFID tag on the cartridge, an electronic microchip on the cartridge,or a combination thereof. The cartridge may comprise one or moreshipping tablets wherein at least one shipping tablet is dispensed priorto dispensing of a dosage form.

The term “C_(max)” as used herein means the maximum observed plasmaconcentration following administration of a drug.

The term “congener” as used herein refers to one of many variants orconfigurations of a common chemical structure.

The term “disintegration” is used interchangeably herein with “erosion”and means the physical process by which a dosage form breaks down andpertains to the physical integrity of the dosage form alone. This canoccur in a number of different ways including breaking into smallerpieces and ultimately, fine and large particulates or, alternatively,eroding from the outside in, until the dosage form has disappeared.

The term “dispensing device”, “drug dispensing device”, “dispenser”,“drug dispenser”, “drug dosage dispenser”, “device” and“drug deliverydevice” are used interchangeably herein and refer to a device thatdispenses a drug dosage form. The dispensing device provides forcontrolled and safe delivery of a pharmaceutically active substance(e.g., an opioid such as sufentanil) formulated in the dosage form. Thedevice may be adapted for storage and/or delivery of a dosage form suchas a lozenge, pill, tablet, capsule, membrane, strip, liquid, patch,film, gel, spray or other form.

The term “dispensing end” as used herein with reference to a devicemeans the portion of the device comprising the proboscis and shroudwhich serves to deliver a drug dosage form to the oral mucosa of asubject.

The term “drug”, “medication”, “pharmacologically active agent”,“therapeutic agent” and the like are used interchangeably herein andgenerally refer to any substance that alters the physiology of an animaland can be effectively administered by the oral transmucosal route.

The term “erosion time” means the time required for a solid dosage formto break down until the dosage form has disappeared.

The term “FOB” refers to a small, portable handheld, powered electronicdocking device that can be used in conjunction with the drug dispensingdevice to upload data, download data, control access to the drugdispensing device, control access to the drug dosage forms, or enhanceor otherwise alter the User interface of the drug dispensing device. AFOB may communicate and dock with a drug dispensing device either in awired or wireless fashion. A FOB may be adapted to attach to a cord soas to allow the FOB to hang from the neck of a healthcare professionalsuch as a physician or caregiver, particularly in the hospital setting.A drug dispensing device may communicate with the physician or caregiver via the FOB.

The terms “formulation” and “drug formulation” as used herein refer to aphysical composition containing at least one pharmaceutically activesubstance, which may be provided in any of a number of dosage forms fordelivery to a subject. The dosage form may be provided to the patient asa lozenge, pill, capsule, membrane, strip, liquid, patch, film, gum,gel, spray or other form.

The term “hydrogel-forming preparation”, means a solid formulationlargely devoid of water which upon contact with an aqueous solution,e.g., a bodily fluid, and in particular that of the oral mucosa, absorbswater in such a way that it forms a hydrated gel in situ. The formationof the gel follows unique disintegration (or erosion) kinetics whileallowing for release of the therapeutic agent over time.

The term “lock-out feature” is used herein with reference to a featureof the device which provides for a “lock-out time”.

The term “lock-out time” is used herein with reference to the period oftime during which the device does not allow drug accessibility, i.e., adosage form cannot be dispensed during the “lock-out time”. “Lock-outtime” may be programmable, a fixed time interval, a predeterminedinterval, a predetermined variable interval, an interval determined byan algorithm or a variable interval communicated to the device from aremote computer or docking station.

The term “Log P” as used herein means logarithm of the ratio ofequilibrium concentrations of un-ionized compound between octanol andwater. P also called the “octanol-water partition coefficient” andserves as a means to quantify the hydrophobicity or lipophilicity of, achemical characteristic of a given drug.

The term “mucoadhesion” is used herein in to refer to the adhesion tomucosal membranes which are covered by mucus, such as those in the oralcavity and may be used interchangeably herein with the term“bioadhesion” which refers to adhesion to any biological surface.

The term “mucosal membrane” refers generally to any of the mucus-coatedbiological membranes in the body. Absorption through the mucosalmembranes of the oral cavity is of particular interest. Thus, oralmucosal absorption, i.e., buccal, sublingual, gingival and palatalabsorption are specifically contemplated.

The term “mucosal-depot” is used herein in its broadest sense to referto a reservoir or deposit of a pharmaceutically active substance withinor just beneath the mucosal membrane.

The term “non-ordered particulate mixture” or “non-ordered mixture” isused herein with reference to a formulation where the mixture is notordered with respect to the pharmaceutically active agent and thebioadhesive material or bioadhesion promoting agent, or otherformulation components. In addition, it is used herein with reference toany formulation prepared by a process that involves dry mixing whereindrug particles are not uniformly distributed over the surface of largercarrier particles. Such ‘non-ordered’ mixing may involve dry mixing ofparticles in a non-ordered fashion, where there is no requirement withrespect to the order of addition/mixing of specific excipients with thedrug, bioadhesive material or bioadhesion promoting agent and/ordisintegrants. Further in the non-ordered mixing process, there is nolimitation on the size of the drug particles. The drug particles may belarger than 25 μm. In addition, a “non-ordered mixture” includes anymixing processes in which the primary carrier particles do notincorporate a disintegrant within. Finally the “non-ordered mixture” maybe prepared by any ‘wet mixing’ processes, i.e. processes in which asolvent or non-solvent is added during the mixing process or any mixingprocess in which the drug is added in a solution or suspension form.

The term “operatively connected” as used herein means the components areprovided in a device so as to function as intended to achieve an aim.For example, a memory device operatively connected to a CPU which isfurther operatively connected to a release mechanism may be meant toindicate that, upon actuation, the CPU communicates with the memorydevice to check the status or history of drug delivery, and then furthercommunicates with the release mechanism (e.g., via a solenoid and aswitch) to release and dispense a drug.

The term “opioid naïve patient” is used herein with reference to apatient who has not received repeated administration of an opioidsubstance over a period of weeks to months.

The term “opioid tolerant patient” as used herein means a physiologicalstate characterized by a decrease in the effects of an opioid substance(e.g., analgesia, nausea or sedation) with chronic administration. Anopioid substance is a drug, hormone, or other chemical substance thathas analgesic, sedative and/or narcotic effects similar to thosecontaining opium or its derivatives. If analgesic tolerance develops,the dose of opioid substance is increased to result in the same level ofanalgesia. This tolerance may not extend to side effects and sideeffects may not be well tolerated as the dose is increased.

The terms “oral transmucosal dosage form” and “drug dosage form” may beused interchangeably herein and refer to a dosage form which comprises apharmaceutically active substance, e.g., a drug such as sufentanil. Theoral dosage form is used to deliver the pharmaceutically activesubstance to the circulation by way of the oral mucosa and is typicallya “sublingual dosage form”, but in some cases other oral transmucosalroutes may be employed. The dosage form provides for delivery of thepharmaceutically active substance across the oral mucosa and bycontrolling the formulation the timing for release of thepharmaceutically active substance can be achieved. The dosage formcomprises pharmaceutically acceptable excipients and may be referred toas a NanoTab™, as detailed in U.S. application Ser. No. 11/650,174,expressly incorporated by reference herein. The dosage form comprises aformulation that is neither effervescent nor does it comprise anessentially water-free, ordered mixture of microparticles of drugadhered to the surface of carrier particles, where the carrier particlesare substantially larger than the microparticles of drug.

The terms “oral transmucosal drug delivery” and “oral transmucosaladministration” as used herein refer to drug delivery that occurssubstantially via the transmucosal route and not via swallowing followedby GI absorption. Maximal delivery occurs via the oral mucosa, typicallyby placement of the dosage form within the sublingual cavity.

The term “proboscis” is used interchangeably with the terms “dispensingtip” a “delivery tip”, and refers to a dispensing and/or positioning tipof a drug dosage form dispenser that delivers a dosage form to the oralmucosa (e.g., the sublingual space).

The term “radio frequency identification device” or “RFID” Is used withreference to an automatic identification method, which relies on storingand remotely retrieving data using devices called RFID tags, wherein theRFID tag is applied to, or incorporated into a product, or person forthe purpose of identification using radiowaves. Some tags can be readfrom several meters away and beyond the line of sight of the reader.

The term “replaceable cartridge” or “disposable cartridge” is used withreference to a cartridge for housing drug dosage forms which istypically configured to hold up to 200 drug dosage forms, wherein thecartridge is designed to be used and discarded.

The term “shipping tablet” is used herein with reference to an“initialization”, or “shipping” tablet which is the same size and shapeas a drug-containing dosage form but does not contain a pharmaceuticallyactive substance. The “shipping tablet” may comprise a placebo dosageform that does not contain a pharmaceutically active substance or may bemade of plastic or other material. It is the first thing dispensed froma new cartridge after insertion into a dispensing device. The device hasa means for differentiating between the shipping tablet and a dosageform containing a pharmaceutically active substance.

The term “shroud” is used to describe a partial or complete covering ofthe dispensing end of the device which protects the delivery port fromcontact with saliva or other moisture in the oral cavity and forms abarrier between the device, the oral mucosa and tongue, has a relief fordosage form delivery, and an interior that is hydrophobic or hydrophilicwhich serves to minimize or eliminate saliva ingress or moistureingress. The “shroud” creates a barrier from the oral mucosa contactingthe valve area and dosage form, aiding in dosage form dispensing anddiscouraging dosage form adherence to the shroud. The shroud may have arounded interior surface or other geometry to stop the dosage formadhering to the shroud. The shroud limits the ability of the tongue orsublingual mucosa to contact the dosage form dispensing area, therebycontrolling saliva contact and ingress.

The term “subject” includes any subject, generally a mammal (e.g.,human, canine, feline, equine, bovine, ungulate etc.), adult or child,in which treatment for a disorder is desired. The terms “subject” and“patient” may be used interchangeably herein.

The term “systems that include a drug dosage form and a dispensingdevice” as used herein refers to a drug dispensing system for deliveryand/or monitoring of drug administration. The system may be used tomonitor and deliver a pharmaceutically active substance, e.g., an opioidsuch as sufentanil, wherein the amount of drug delivered, correspondingefficacy and safety are enhanced over currently available systems. Thesystem may have one or more features that provide for improved safetyand ease of use over currently available systems including a securityfeature that prevents unauthorized access to the stored drugs, a dosinglock-out feature, a means for identifying an individual patient forcontrolled drug access, a dose counting feature, a memory means forretaining information about dose delivery, and an interface forbidirectional exchange of information with a user, a drug cartridge, oranother device such as a computer.

The term “small volume drug dosage form” or “small volume dosage form”is used herein with reference to a small volume dosage form that has avolume of less than 100 μl and a mass of less than 100 mg. Morespecifically, the dosage form has a mass of less than 100 mg, 90 mg, 80mg, 70 mg, 60 mg, 50 mg, 40 mg, 30 mg, 29 mg, 28 mg, 27 mg, 26 mg, 25mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16 mg, 15mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg or 5 mg ora volume of less than 100 μl, 90 μl, 80 μl, 70 μl, 60 μl, 50 μl, 40 μl,30 μl, 29 μl, 28 μl, 27 μl, 26 μl, 25 μl, 24 μl, 23 μl, 22 μl, 21 μl, 20μl, 19 μl, 18 μl, 17 μl, 16 μl, 15 μl, 14 μl, 13 μl, 12 μl, 11 μl, 10μl, 9 μl, 8 μl, 7 μl, 6 μl or 5 μl. The “dosage form” may or may nothave bioadhesive characteristics and may form a hydrogel upon contactwith an aqueous solution.

The “dosage form” may be used to deliver any drug that can beadministered by the oral transmucosal route in an amount amenable toadministration via the small size of the dosage form, i.e. 0.25 μg to99.9 mg, 1 μg to 50 mg or 1 μg to 10 mg.

The term “small volume sufentanil-containing drug dosage form” is usedherein with reference to a small volume dosage form that contains a doseof sufentanil selected from about 2 micrograms (mcg) to about 200 mcg ofsufentanil, e.g., 5 mcg, 10 mcg, 15 mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg,60 mcg, 70 mcg, 80 mcg or 100 mcg of sufentanil.

The term “solid dosage form” or “solid drug dosage form” is used hereinwith reference to a small volume dosage form that is a solid, e.g., alozenge, a pill, a tablet, a membrane or a strip.

The term “sublingual”, means literally “under the tongue” and refers toadministering a drug dosage form via the mouth in such a way that thepharmaceutically active substance is rapidly absorbed via the bloodvessels under the tongue rather than via the digestive tract. Absorptionoccurs via the highly vascularized sublingual mucosa and allows thepharmaceutically active substance more direct access to the bloodcirculation, providing for direct systemic administration independent ofGI influences.

The term “terminal half-life” or “t_(1/2) [h]” as defined herein iscalculated as ln(2)/λ_(z) (defined as the first order terminal rateconstant estimated by linear regression of the time versus logconcentration curve) and also determined after the final dosing inrepeated dose studies.

The term “T_(max)” as used herein means the time point of maximumobserved plasma concentration.

The term “T_(onset)” as used herein means the observed “time of onset”and represents the time required for the plasma drug concentration toreach 50% of the maximum observed plasma concentration, C_(max).

The term “therapeutically effective amount” means an amount of atherapeutic agent, or a rate of delivery of a therapeutic agent (e.g.,amount over time), effective to facilitate a desired therapeutic effect,such as pain relief. The precise desired therapeutic effect (e.g., thedegree of pain relief, and source of the pain relieved, etc.) will varyaccording to the condition to be treated, the tolerance of the subject,the drug and/or drug formulation to be administered (e.g., the potencyof the therapeutic agent (drug), the concentration of drug in theformulation, and the like), and a variety of other factors that areappreciated by those of ordinary skill in the art.

The term “transmucosal” delivery of a drug and the like is meant toencompass all forms of delivery across or through a mucosal membrane. Inparticular, “oral transmucosal” delivery of a drug includes deliveryacross any tissue of the mouth, pharynx, larynx, trachea, or uppergastrointestinal tract, particularly including the sublingual, gingivaland palatal mucosal tissues.

III. Drug Dosage Forms

The claimed small volume sublingual drug dosage forms produce a reducedsaliva response as compared with conventional, larger dosage forms thatare intended to deliver a drug in the oral cavity.

The preferred site for oral transmucosal drug delivery is the sublingualarea, although in certain embodiments it may be advantageous for thedosage form to be placed inside the cheek, or to adhere to the roof ofthe mouth or the gum.

Sublingual delivery is preferred as the sublingual mucosa is morereadily permeable to medications than other mucosal areas, such as thebuccal mucosa, resulting in more rapid uptake.

The dosage forms provide for the delivery of a greater percentage (andamount) of the drug via the oral mucosa and a corresponding decrease indelivery via the gastrointestinal (GI) tract as compared to traditionaloral dosage forms and other oral transmucosal dosage forms.

Typically, the dosage forms are adapted to adhere to the oral mucosa(i.e. are bioadhesive) during the period of drug delivery, and untilmost or all of the drug has been delivered from the dosage form to theoral mucosa.

More specifically, the dosage forms have a mass of less than 100 mg, 90mg, 80 mg, 170 mg, 60 mg, 50 mg, 40 mg, 30 mg, 29 mg, 28 mg, 27 mg, 26mg, 25 mg, 24 mg, 23 mg, 22 mg, 21 mg, 20 mg, 19 mg, 18 mg, 17 mg, 16mg, 15 mg, 14 mg, 13 mg, 12 mg, 11 mg, 10 mg, 9 mg, 8 mg, 7 mg, 6 mg or5 mg or a volume of less than 100 μl, 90 μl, 80 μl, 70 μl, 60 μl, 50 μl,40 μl, 30 μl, 29 μl, 28 μl, 27 μl, 26 μl, 25 μl, 24 μl, 23 μl, 22 μl, 21μl, 20 μl, 19 μl, 18 μl, 17 μl, 16 μl, 11 μl, 14 μl, 13 μl, 12 μl, 11μl, 10 μl, 9 μl, 18 μl, 7 μl, 6 μl or 5 μl.

In a preferred embodiment, the claimed dosage forms have a mass of lessthan 30 mg and a volume of less than 30 ul.

The dosage forms typically have bioadhesive characteristics and may forma hydrogel upon contact with an aqueous solution.

The dosage forms typically have an erosion time of from about 6 minutesor up to 25 minutes, however the erosion time may vary. Morespecifically, the dosage forms typically have an erosion time of about 5minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23minutes, 24 minutes or 25 minutes.

In general, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 98% or at least 99% of the total amount of pharmaceutically activesubstance in a dosage form administered to the oral mucosa of a subjectis absorbed via the oral transmucosal route.

The dosage forms may have essentially any shape, examples of whichinclude a round disc with a flat, concave, or convex face, an ellipsoidshape, a spherical shape, a polygon with three or more edges and flat,concave, or convex faces. The dosage forms may be symmetrical orasymmetrical, and may have features or geometries that allow forcontrolled, convenient, and easy storage, handling, packaging or dosing.

Oral transmucosal drug delivery is simple, non-invasive, and can beaccomplished by a caregiver or patient with minimal discomfort. A dosageform for oral transmucosal delivery may be solid or non-solid. In onepreferred embodiment, the dosage from is a solid that turns into ahydrogel following contact with saliva. In another preferred embodiment,the dosage from is a solid that erodes without forming a hydrogelfollowing contact with saliva.

Generally, oral transmucosal delivery of pharmaceutically activesubstances is achieved using solid dosage forms such as lozenges ortablets, however, liquids, sprays, gels, gums, powders, and films andthe like may also be used.

For certain drugs, such as those with poor bioavailability via the GItract, e.g., lipophilic opioids such as sufentanil, oral transmucosaldelivery is a more effective delivery route than GI delivery. For suchlipophilic drugs, oral transmucosal delivery has a shorter onset time(i.e., the time from administration to therapeutic effect) than doesoral GI delivery and provides better bioavailability and more consistentpharmacokinetics.

The small size of the claimed drug dosage forms is designed to reducethe saliva response, thus reducing the amount of drug swallowed, andthereby delivering a substantial amount of drug to a subject via theoral mucosa. The claimed drug dosage forms provide for efficaciousdelivery of sufentanil via the oral mucosa and a consistent plasma levelwithin the therapeutic window.

Formulations for preparation of the claimed dosage forms and methods ofmaking them are described in U.S. application Ser. Nos. 11/825,251 and11/650,227, expressly incorporated by reference herein. An exemplaryformulation is bioadhesive and comprises from about 0.0004% to about0.04% sufentanil, e.g., 0.0005%, 0.001%, 0.002%, 0.003%, 0.004%, 0.006%,0.008%, 0.01%, 0.012%, 0.014% or 0.016% sufentanil. In general, theformulation comprises (a) a non-ordered mixture of a pharmaceuticallyactive amount of a drug; (b) a bioadhesive material which provides foradherence to the oral mucosa of the subject; and (c) stearic acid,wherein dissolution of a dosage form comprising the formulation isindependent of pH, e.g., over a pH range of about 4 to 8.

Numerous suitable nontoxic pharmaceutically acceptable carriers for usein oral dosage forms can be found in Remington's PharmaceuticalSciences, 17th Edition, 1985.

It will be understood that the formulation is converted into a dosageform for delivery to a subject using procedures routinely employed bythose of skill in the art, such as direct compression, wet granulation,etc. The process for preparation of the dosage form is optimized foreach formulation in order to achieve high dose content uniformity.

While not wishing to be bound by theory, when a claimed dosage form isplaced in the sublingual cavity, preferably under the tongue on eitherside of the frenulum linguae, it adheres upon contact. As the dosageform is exposed to the moisture of the sublingual space the dosage formabsorbs water, resulting in erosion of the dosage form and release ofthe drug to the circulation of the subject.

IV. Sufentanil

Opioids are widely used for the treatment of pain, and are generallydelivered intravenously, orally, epidurally, transdermally, rectally andintramuscularly. Morphine and its analogues are commonly deliveredintravenously and are effective against severe, chronic and acute pain.However, they can also have severe respiratory depressive effects if notused appropriately and also suffer from a high abuse potential. Thepredominant cause of morbidity and mortality from pure opioid overdosesis due to respiratory complications.

Sufentanil(N-[(4-(Methoxymethyl-1-(2-(2-thienyl)ethyl)-4-piperidinyl)]-N-phenylpropanamide),is used as a primary anesthetic, to produce balanced general anesthesiain cardiac surgery, for epidural administration during labor anddelivery and has been administered experimentally in both intranasal andliquid oral formulations. A commercial form of sufentanil used for IVdelivery is the SUFENTA FORTE® formulation. This liquid formulationcontains 0.075 mg/ml sufentanil citrate (equivalent to 0.05 mg ofsufentanil base) and 9.0 mg/ml sodium chloride in water. It has a plasmaelimination half-life of 148 minutes, and 80% of the administered doseis excreted in 24 hours.

The use of sufentanil clinically has predominantly been limited to IVadministration in operating rooms or intensive care units. There havebeen a few studies on the use of liquid sufentanil preparations forlow-dose intranasal administration (Helmers et al., 1989; Jackson K, etal., 3 Pain Symptom Management 2002: 23(6): 450-452) and case reports ofsublingual delivery of a liquid sufentanil preparation (Gardner-Nix J.,3 Pain Symptom Management. 2001 August; 22(2):627-30; Kunz K M, TheisenJ A, Schroeder M E, Journal of Pain and Symptom Management, 8:189-190,1993). In most of these studies, the smallest dosing of sufentanil inadults was 5 mcg in opioid naïve patients. Liquid administered to theoral or nasal mucosa suffers from lower bioavailability and possibly ashorter duration of action as demonstrated by the animal studies(sublingual liquid) described herein, as well as the literature (nasalliquid drops—Helmers et al., 1989). Gardner-Nix provides analgesic data(not pharmacokinetic data) produced by liquid sublingual sufentanil anddescribes the analgesic onset of liquid sublingual sufentanil occurringwithin 6 minutes but the duration of pain relief lasted onlyapproximately 30 minutes.

A number of opioid dosage forms many of which contain fentanyl arecurrently available for treatment of pain.

Following transbuccal administration of fentanyl using a lozenge (e.g.,Actiq®), the bioavailability is 50%, although the T_(max) for the 200mcg dosage of Actiq® ranges from 20-120 minutes resulting from erraticGI uptake due to the fact that 75% of the fentanyl is swallowed (Actiq®package insert). More recent publications on the T_(max) of Actiqindicate that these original times were skewed towards more rapid onset(Fentora package insert indicates a range of T_(max) for Actiq extendingup to 240 minutes). Fentora (a fentanyl buccal tablet) exhibits abioavailability of 65%, with reported swallowing of 50% of the drug. Incontrast to the claimed dosage forms, both Actiq® and Fentora sufferfrom the disadvantage that substantial amounts of lozenge-administeredfentanyl are swallowed by the patient.

Sufentanil and fentanyl have many similarities as potent mu-opioidreceptor agonists, however, they have been shown to differ in many keyways. Multiple studies have demonstrated sufentanil to be in the rangeof 7-24 times more potent than fentanyl (SUFENTA® package insert; PaixA, et al. Pain, 63:263-69, 1995; Reynolds L, et al., Pain, 110:182-188,2004). Therefore, sufentanil may be administered using a smaller dosageform, avoiding the increased saliva response of a larger dosage form andthereby minimizing the amount of drug that is swallowed. This leads tominimal GI uptake.

In addition, fentanyl and other opiate agonists, have the potential fordeleterious side effects including respiratory depression, nausea,vomiting and constipation.

There is evidence which suggests that sufentanil may have lessrespiratory depression than fentanyl and other opioids at clinical doses(Ved et al., 1989; Bailey at al., 1990; Conti et al., 2004).

Since fentanyl has a 30% bioavailability from the GI route, swalloweddrug can contribute to the C_(max) plasma levels to a significant degreeand results in the erratic C_(max) and T_(max) observed with theseproducts. In contrast, the bioavailability of sufentanil from the GIroute is 10-12%, and therefore swallowed drug will not contribute to theC_(max) plasma levels to a significant degree.

Further, the lipid solubility (octanol-water partition coefficient) ofsufentanil (1778:1) is greater than fentanyl (816:1) (van den Hoogen andColpaert, Anesthes. 66:186-194, 1987). Sufentanil also displaysincreased protein binding (91-93%) compared with fentanyl (80-85%)(SUFENTA® and Actiq® package inserts, respectively). Sufentanil has apKa of 8.01, whereas the pKa of fentanyl is 8.43 (Paradis et al.,Therapeutic Drug Monitoring, 24:768-74, 2002). These differences canaffect various pharmacokinetic parameters, for example, sufentanil hasbeen shown to have a faster onset of action and faster recovery timethan fentanyl (Sanford et al., Anesthesia and Analgesia, 65:259-66,1986). As compared to fentanyl, use of sufentanil can result in morerapid pain relief with the ability to titrate the effect and avoidoverdosing.

Importantly, sufentanil has been shown to produce endocytosis of themu-opioid receptor 80,000 times more potently than fentanyl (Koch etal., Molecular Pharmacology, 67:280-87, 2005). The result of thisreceptor internalization is that neurons continue to respond tosufentanil more robustly over time than with fentanyl, suggesting thatclinically less tolerance would develop to sufentanil compared tofentanyl with repeated dosing.

Prior to the work of the current inventors, no pharmacokinetic data hadbeen published on sublingual sufentanil in any form. Pharmacokineticdata for ocular and intranasal transmucosal delivery of sufentanil hasbeen published based on studies in dogs and humans. Farnsworth et al.(Anesth Analg, 1998, 86:138-140) describe ocular transmucosal absorptionand toxicity of sufentanil in dogs, where 50 mcg of sufentanil wasadministered over a period of 2.5 minutes to the conjuctiva of fiveanesthetized dogs. The T_(max) occurred at 5 min with a C_(max) of 0.81ng/mL and a t_(1/2) of approximately 18 minutes. A study report ofintranasal and intravenous administration of 15 mcg of sufentanil in 16humans provides a comparison of pharmacokinetic profiles, whereintranasal sufentanil was delivered via 3 drops in each nostril with 2.5mcg/drop. Intranasal sufentanil had a 78% bioavailability based on theAUC from 0-120 minutes compared with intravenous delivery. Intranasaldelivery resulted in a T_(max) of 10 minutes with a C_(max) of 0.08ng/mL. The t_(1/2) was approximately 80 minutes. See, Helmers et al.,Can J Anaesth. 6:494-497, 1989. A third study in pediatric patientsdescribes preoperative intranasal dosing of 15 children with 2 mcg/kgsufentanil via nasal drops and with plasma levels of sufentanil measuredstarting at 15 minutes, which was too late to capture the T_(max). Basedon extrapolation of the data, the C_(max) was approximately 0.3 ng/mLand the t_(1/2) was approximately 75 minutes (Haynes et al., Can JAnaesth. 40(3):286, 1993).

Sufentanil Dosage Forms

The active agent in the claimed dosage forms is sufentanil, alone or incombination with a sufentanil congener such as alfentanil, fentanyl,lofentanil, carfentanil, remifentanil, trefentanil, or mirfentanil. In apreferred embodiment, sufentanil alone is the active agent. Sufentanilmay be provided in the claimed dosage forms in any of a number offormulations. Sufentanil may be provided as sufentanil citrate,sufentanil base, or a combination thereof.

A sufentanil drug dosage form may contain from about 0.25 to about 200mcg of sufentanil per dosage form for sublingual delivery. In oneexemplary embodiment, each dosage form contains from about 0.25 to about200 mcg of sufentanil, alone or combination with one or more othertherapeutic agents or drugs.

Exemplary drug dosage forms for administration to children (pediatricpatients) contain from about 0.25 to about 120 mcg of sufentanil perdosage form. For example, a drug dosage form for administration tochildren may contain about 0.25, 0.5, 1, 2.5, 4, 5, 6, 8, 10, 15, 20,40, 60 or 120 mcg of sufentanil for oral transmucosal delivery. Itfollows that for pediatric patients, an exemplary dose range is from atleast about 0.02 mcg/kg to about 0.5 mcg/kg with a preferable range offrom about 0.05 to about 0.3 mcg/kg.

Exemplary drug dosage forms for administration to adults contain fromabout 2.5 to about 200 mcg of sufentanil per dosage form. For example, adrug dosage form for administration to adults may contain about 2.5, 3,5, 7.5, 10, 15, 20, 40, 60, 80, 100, 120, 140, 180 or 200 mcg or more ofsufentanil for oral transmucosal delivery.

Preferably, a sufentanil-containing dosage form comprises from about 5to about 100 micrograms (mcg) of sufentanil, e.g., 5 mcg, 10 mcg, 15mcg, 20 mcg, 30 mcg, 40 mcg, 50 mcg, 60 mcg, 70 mcg, 80 mcg or 100 mcgof sufentanil.

As will be understood by those of skill in the art, the dose will be onthe low end of the range for children and the high end of the range foradults dependent upon body mass, in particular when administered longterm to opioid-tolerant adults. Prior to the work of the currentinventors, small-volume sufentanil-containing dosage forms for oraltransmucosal drug delivery had not been described.

In various embodiments, the claimed dosage forms provide effective painrelief in all types of patients including children, adults of all ageswho are opioid tolerant or naïve and non-human mammals. The inventionfinds utility in both the inpatient and outpatient setting and in thefield.

Congeners of Sufentanil

Congeners of sufentanil find use in the compositions, methods andsystems described herein, examples of which include alfentanil,lofentanil, carfentanil, remifentanil, trefentanil or mirfentanil.

In certain embodiments, the dosage form comprises at least 0.005% to asmuch as 99.9% by weight of alfentanil, lofentanil, carfentanil,remifentanil, trefentanil or mirfentanil. The percentage of activeingredient(s) will vary dependent upon the size of the dosage form andnature of the active ingredient(s), optimized to obtain maximal deliveryvia the oral mucosal route. In some aspects of the invention, more thanone active ingredient may be included in a single dosage form.

V. Treatment of Pain

Using current treatment methods, pain control is attempted using anumber of interventions, which generally include: patient-controlledanalgesia (PCA), continuous epidural infusion (CEI), other types ofacute pain control, palliative care pain control, and home healthpatient pain control. These methods meet with varying degrees of successwith respect to duration of control, ease of treatment and safety versusside effects.

The need for rapid treatment of acute pain occurs in many differentclinical situations, including post-operative recuperation, rheumatoidarthritis, failed back, end-stage cancer (i.e., breakthrough pain), etc.Post-operatively, for example, patients suffer from severe pain for thefirst few days followed by days of mild to moderate levels of pain.

The most common analgesic used to treat moderate to severepost-operative pain is IV morphine. This is either delivered on an “asneeded” basis to the patient by a nurse using IV injection or commonly amorphine syringe is placed in a PCA pump and the patientself-administers the opioid by pressing a button which has a lock-outfeature. Other opioids, such as hydromorphone and fentanyl may also beadministered in this manner.

Treatment of acute pain is also necessary for patients in an outpatientsetting. For example, many patients suffer from chronic pain and requirethe use of opioids on a weekly or daily basis to treat their pain. Whilethey may have a long-acting oral or transdermal opioid preparations totreat their chronic underlying pain levels, they often need short-actingpotent opioids to treat their severe breakthrough pain levels.

Treatment of acute pain is also necessary “in the field” under highlysub-optimal conditions. Paramedics or military medics often are requiredto treat severe acute pain in un-sterile situations, where needles usedfor IV or IM administration can result in unintended needle sticks, riskof infection, etc. Oral opioid tablets often take 60 minutes to providerelief which is too long for someone in severe pain.

In a number of clinical settings, there is dearly a need for improvedmeans to administer a drug that produces effective pain relief in amanner that is titratable, safe and convenient, and non-invasive thatprovides relief from acute, severe breakthrough or intermittent painover an appropriate period of time.

The claimed compositions, methods and systems rely on administration ofdosage forms comprising a pharmaceutically active substance such assufentanil which is effective for the treatment of acute pain (i.e.post-operative pain), intermittent pain or breakthrough pain, using adispensing device that includes features such as lock-out, a means forpatient identification prior to drug administration and a means toprotect the dosage forms stored in the dispensing device. The claimedmethods and systems thereby provide significant advantages overcurrently available treatment modalities in terms of both safety andefficacy.

VI. In Vivo Human Studies

Provided herein is pharmacokinetic data obtained in humans based onstudies where sufentanil was administered via the sublingual route usingthe claimed small volume dosage forms.

Two human clinical studies were performed using healthy humanvolunteers. The first study which is detailed in Example 1 was performedwith 12 subjects (6 men and 6 women) using slow-eroding sublingualsufentanil dosage forms containing either 2.5 mcg, 5 mcg or 10 mcg ofsufentanil base corresponding to 3.7 mcg, 7.5 mcg or 15 mcg ofsufentanil citrate, respectively in comparison to a 10-minute IVinfusion of 5 mcg sufentanil or 4 repeated doses of a slow-erodingsublingual sufentanil dosage form containing 5 mcg sufentaniladministered at 10-minute intervals (Table 1). The second study which isdetailed in Example 2 was performed with 11 subjects usingfaster-eroding sublingual sufentanil dosage forms containing either 10mcg or 80 mcg of sufentanil base corresponding to 15 mcg or 120 mcg ofsufentanil citrate, respectively, in comparison to a 10-minute IVinfusion of 10 mcg sufentanil or a 20-minute IV infusion of 50 mcgsufentanil, a sublingual dose of 5 mcg of sufentanil solution or 4repeated administrations of fast-eroding sublingual sufentanil dosageforms containing 10 mcg of sufentanil administered at 20-minuteintervals (Table 2). All excipients were “pharmaceutically acceptable”(inactive) and have GRAS or “generally recognized as safe” status.

Sufentanil dosage forms designed for sublingual use were compared to IVsufentanil, administered through an IV catheter as a continuousinfusion. Plasma samples were drawn from a different IV catheter at aremote location. The assay demonstrated good inter-day precision andaccuracy at the high, medium and low quality control sampleconcentrations.

The dosage forms for the first study eroded over a period of 15-25minutes in all subjects and are designated herein as “slow-eroding”. Thedosage forms for the second study eroded over a period of 6-12 minutesin all subjects and are designated herein as “faster-eroding”. Afterplacement of each sufentanil dosage form in the sublingual cavity of thehealthy volunteers, a remarkably consistent pharmacokinetic profile wasobtained. The bioavailability of sufentanil administered using smallvolume sublingual dosage forms as compared to IV administration forsingle and multiple administrations was high and ranged from 60.9% (10mcg dose; faster-eroding) to 97.2% (4×5 mcg dose (slow-eroding). Thebioavailability of sufentanil administered using small volume sublingualdosage forms is greater than that of the fentanyl products, Actiq andFentora (47% and 65%, respectively—Fentora package insert). Importantly,the bioavailability is linked to the consistency of total drug deliveredto the patient. For example, the total plasma drug area under the curve(AUC 0-infinity) for sufentanil dosage forms 10 mcg was 0.0705±0.0194hr*ng/ml (mean±standard deviation (SD)). This SD is only 27.5% of thetotal AUC. Coefficient of variation (CV) is a term to describe thepercent SD of the mean. The coefficient of variation for the fentanylproducts, Fentora (AUC is 45%) and Actiq (AUC is 41%; Fentora packageinsert), while the coefficient of variation around the bioavailabilityof sufentanil administered using small volume sublingual dosage forms isless than 40%. Therefore, the total dose delivered to the subject is notonly more bioavailable for the sufentanil dosage forms but it is moreconsistent.

Although this high bioavailability could be due to a number of factorsincluding but not limited to erosion time, it is likely that the lack ofsaliva produced by the small size of the dosage forms limits theswallowing of the drug and avoids the low bioavailability typical ofdrug absorption via the GI route. Both Fentora and Actiq package insertsclaim at least 50% and 75% of the drug dose, respectively, is swallowedvia the saliva, and both exhibit lower bioavailability than the claimeddosage forms.

The dosage forms used in the clinical trials had a volume ofapproximately 5 microliters (mass of 5.5-5.85 mg), a small fraction ofthe size of Actiq or Fentora lozenges. Therefore, less than 25% of thedrug is swallowed, which is a much lower percentage than is swallowedwith Fentora or Actiq.

The sufentanil sublingual dosage forms are also superior in terms ofconsistent drug plasma levels early after administration. The C_(max)obtained with the 10 mcg sufentanil dosage form was 27.5±7.7 pg/ml. Thecoefficient of variation of the C_(max) is therefore only 28%. TheC_(max) for Fentora and Actiq suffer from variability of GI uptake ofdrug. Fentora reports a C_(max) of 1.02±0.42 ng/ml, therefore thecoefficient of variation of the C_(max) is 41%. The range ofcoefficients of variation for the various doses of Fentora is from 41%to 56% (package insert). The Actiq coefficient of variation of C_(max)is reported as 33% (Fentora package insert).

In addition to superior bioavailability and consistency in plasmaconcentrations, the T_(max) for 10 mcg sufentanil dosage forms was40.8±13.2 minutes (range 19.8-60 minutes). The reported average T_(max)for Fentora is 46.8 with a range of 20-240 minutes. The T_(max) forActiq is 90.8 minutes, range 35-240 minutes (Fentora package insert).Therefore, the consistency in onset of analgesia for sufentanil dosageforms is markedly better than that of Fentora and Actiq.

In addition, the T_(max) values obtained following repeated sublingualadministration of the claimed sufentanil dosage forms were significantlyshorter than those observed following administration of a singlesublingual sufentanil dosage form. Most notably, the T_(max) obtainedwith repeat dosing of 10 μg (4×10 μg) sufentanil dosage forms(fast-eroding) occurred 24.6 minutes after the previous (fourth) dose.The coefficient of variation around T_(max) was only 18%, indicating avery consistent and predictable T_(max) with repeated sublingualadministration of the claimed sufentanil dosage forms.

The linearity of sufentanil plasma levels following sublingualadministration of the claimed sufentanil dosage forms doses wasconsistent from the 25 mcg dose up through the 80 mcg dose.

Although still in development, published data allows comparison of thesufentanil pharmacokinetic data provided herein to that of Rapinyl, afentanyl sublingual fast-dissolve lozenge. The coefficient of variationaround the AUC for all three doses of sufentanil exemplified herein (2,5, and 10 mcg) averaged 28.6%, demonstrating that the observed lowcoefficient of variation is not dependent on dose. In contrast, thepublished bioavailability for a sublingual fentanyl product, Rapinyl, isapproximately 70% (Bredenberg, New Concepts in Administration of Drugsin Tablet Form, Acta Universitatis Upsaliensis, Uppsala, 2003). Thecoefficient of variation of the AUC (0-infinity) for Rapinyl ranges from25-42% and is dose-dependent.

In addition, the coefficient of variation of the C_(max) for Rapinylvaries from 34-58% depending on dose. As shown by the data presentedherein, administration of the 10 mcg sufentanil dosage form resulted ina C_(max) variation of only 28%, and the average coefficient ofvariation of C_(max) for the 2, 5, and 10 mcg doses was 29.4%,indicating minimal variability depending on dose. Similarly, thecoefficient of variation for T_(max) with Rapinyl ranges from 43-54%depending on dose, whereas for our sufentanil dosage forms, thiscoefficient of variation for T_(max) averages only 29% over all threedosage strengths. This consistent onset of action achieved withsublingual sufentanil dosage forms allows a safer redosing window whencompared to any of the three comparator drugs, since rising plasmalevels are contained to a shorter period.

Additionally, as with Fentora and Actiq, Rapinyl demonstrates a longerplasma elimination half-life (5.4-6.3 hours, depending on dose) than theclaimed sufentanil dosage forms. The plasma elimination half-life ofsufentanil dosage forms ranged from 1.5-2 hours following a single oraltransmucosal administration in humans (Table 2), which allows for moretitratability and avoids overdosing. As will be understood by those ofskill in the art, the half-life described herein for the exemplifieddosage forms may be adjusted by modification of the component andrelative amounts of the excipients in the formulation used to make agiven dosage form. The ability to titrate to higher plasma levels byadministering repetitive doses of the sublingual sufentanil dosage formswas also tested in this human study.

The methods and systems described herein are designed to workeffectively in the unique environment of the oral cavity, providing forhigher levels of drug absorption and pain relief than currentlyavailable systems. The claimed methods and systems are designed to avoidthe high peak plasma levels of intravenous administration by entry intothe circulation via the sublingual mucosa.

The claimed methods and systems further provide for independent controlof bioadhesion, dosage form disintegration (erosion) and drug releaseover time, together with administration using a device to provide a safedelivery profile. The device-administered sublingual dosage formsprovide individual, repetitive doses that include a defined amount ofthe active agent (e.g., sufentanil), thereby allowing the patient orcare giver to accurately titrate the amount of drug delivered and toadjust the amount as appropriate in a safe and effective manner. Thelock-out feature of the dispensing device adds to the safety of the drugdelivery profile.

Further, treatment with the claimed compositions, methods and systemsprovides for improved safety by minimizing the potentially deleteriousside effects of the peaks and troughs in the plasma drugpharmacokinetics, which are typical of currently available medicationsor systems for treatment of pain.

Advantages of the claimed sublingual dosage forms over various liquidforms for either sublingual or intranasal administration include localrelease of drug from the dosage form over time with minimal swallowingof liquid drug via either the nasal or oral/GI route.

Due to the small size of the oral transmucosal dosage forms, repeatedplacement in the sublingual cavity over time is possible. Minimal salivaproduction and minimal physical discomfort occurs due to the small size,which allows for repetitive dosing over days to weeks to months. Giventhe lipid profile of the sublingual cavity, the sublingual route, alsoallows for slower release into the plasma for certain drugs, such assufentanil, which may be due to utilization of a “depot” effect thatfurther stabilizes plasma levels compared to buccal delivery.

The oral transmucosal dosage forms are designed to fit comfortably underthe tongue such that the drug form erodes sufficiently slowly to avoidthe Immediate peak plasma levels followed by significant drop off seenin prior art formulations such as described in U.S. Pat. No. 6,759,059(Rapinyl), wherein fentanyl was administered via tablets containing 400mcg of fentanyl which resulted in a peak plasma level of 2.5 ng/mlfollowed by an immediate drop in plasma level. Fentora (fentanyl buccaltablet) also suffers from a lack of a plateau phase but rather has asteep incline up to the C_(max) followed by a significant drop-off inplasma levels (Fentora package insert).

VII. Utility of Small-Volume Oral Transmucosal Dosage Forms

The claimed dosage forms, methods and systems find utility in deliveryof sufentanil via the sublingual route for treatment of pain. The smallvolume of the sublingual dosage forms provide for high bioavailability,low variability in T_(max) low variability in C_(max) and lowvariability in AUC. The dosage forms also provide for prolonged plasmalevels within the therapeutic window.

More specifically, the claimed dosage forms, methods and systems providethe advantages that:

-   -   (a) there is a linear relationship between sufentanil plasma        levels in a subject following administration of the claimed        sufentanil dosage forms and the amount of sufentanil in the        dosage form;    -   (b) a single sublingual administration of the claimed sufentanil        dosage forms to a subject results in an AUC_(inf) with a        coefficient of variation of less than 40%;    -   (c) a single or repeated sublingual administration of the        claimed sufentanil dosage forms to a subject results in a        T_(max) with a coefficient of variation of less than 40%;    -   (d) repeated sublingual administration of the claimed sufentanil        dosage forms to a subject results in a bioavailability that is        greater than the bioavailability following a single sublingual        administration to said subject;    -   (e) the difference between the T_(max) following repeated        sublingual administration of the claimed sufentanil dosage forms        and the time of the previous sublingual administration is        shorter than the T_(max) following a single sublingual        administration to the subject;    -   (f) there is a linear relationship between C_(max) and the        amount of sufentanil in the dosage form;    -   (g) there is a linear relationship between AUC_(inf) and the        amount of sufentanil in the dosage form; and    -   (h) the highest predicted steady-state sufentanil concentration        following multiple administrations of 10 or 15 mcg sublingual        sufentanil dosage forms is predictable allowing for an accurate        determination of safe lock-out times and therefore safe and        efficacious treatment of pain.

In one exemplary embodiment described in detail herein, the dosage formsfind utility in treating a subject suffering from pain that may beassociated with any of a variety of identifiable or unidentifiableetiologies. In this embodiment, the dosage forms find utility insuppression or mitigation of pain. The term “treatment” or “management”of pain is used here to generally describe regression, suppression, ormitigation of pain so as to make the subject more comfortable, asdetermined for example by pain score.

The invention finds utility in the treatment of both opioid naïvepatients and opioid tolerant patients.

The dosage forms find particular utility in the treatment of acute pain,such as post-operative pain, as well as other pain, such as “in thefield”, i.e., under highly sub-optimal conditions.

Paramedics or military medics often are required to treat severe acutepain or other injuries or conditions in non-sterile situations, whereneedles used for IV or IM administration can result in unintended needlesticks, risk of Infection, etc. Oral opioid tablets often take 60minutes to provide relief which is too long for someone in severe pain.The claimed dosage forms find utility in addressing this need.

When the dosage forms are used for the treatment of pain, the claimedmethods and systems find utility in administration of drugs to pediatricand adult populations and in treatment of human and non-human mammals,as well as in opioid tolerant and opioid naïve patient populations.

Application of the claimed methods and systems is not limited to anyparticular therapeutic indication. As such, the claimed dosage formsfind utility in administration of sufentanil to pediatric and adultsubjects and in the treatment of human and non-human mammals.

The dosage forms find utility in pediatric applications, since thecomfortable and secure nature of the dosage form allows children toreadily accept this mode of therapy and will reliably deliver drugtransmucosally. Specific examples include, but are not limited to,treatment of pediatric acute pain when IV access is not available orinconvenient, treatment of pediatric asthma when the child is not ableto use an inhaled route of administration effectively, treatment ofnausea when a child can not or will not swallow a pill, pre-proceduralsedation when a child is NPO (no oral intake allowed) or a more rapidonset is required.

The dosage forms find further utility in veterinary applications.Specific examples include, but are not limited to, any treatment of anacute condition for which IV administration is not readily available orinconvenient, such as pain relief, anxiety/stress relief, pre-proceduralsedation, etc.

VIII. Dispensing Devices

Dispensing devices and systems for oral transmucosal administration ofsmall volume drug dosage forms are provided. The dispensing devices arehandheld and portable and comprise a housing having a dispensing endwhich typically has a proboscis with a shroud that provide a means forblocking or retarding saliva ingress and/or moisture control. Thedispensing devices further provide safety features such as a means forlock-out and a means for patient identification.

The claimed dispensing devices, methods and systems comprise delivery ofsmall volume dosage forms to the oral mucosa. The invention is notlimited to the specific devices, systems, methodology and dosage formsdetailed herein, as these may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to limit thescope of the present invention.

Blocking/Retarding Saliva and Moisture Ingress

The claimed dispensing devices comprise a means for minimizing oreliminating saliva ingress and moisture ingress into the dispensingdevice: (1) to avoid wetting the dosage forms therein; (2) to isolateany saliva that enters the dispensing device in such a manner that thedosage forms therein remain dry; (3) to absorb or adsorb any saliva thatenters the dispensing device in such a manner that the dosage formsremain dry; (4) to block saliva and moisture from entering the device toprotect the dosage forms from vapor and liquid phase moisture, or (5)any combination thereof.

The dispensing device has a means for preventing and/or controllinghumidity ingress due to ambient conditions outside of the device.

The means for minimizing or eliminating saliva ingress or preventingother moisture from entering the dispensing device includes, but is notlimited to, one or more flexible or rigid seals, one or more flexible orrigid wipers, use of one or more absorbent material components such as adesiccant or pad, a door or latch that is manually or automaticallyopened and dosed, multiple stage delivery systems, a positive airpressure and airflow, or an air gap or prescribed distance orbarrier/shroud maintained between the dosage form delivery orifice andthe mucous membrane tissues within the mouth that may transport thesaliva. The shroud limits the ability of the tongue or sublingual mucosato contact the dosage form dispensing area, thereby controlling salivacontact and ingress. By inhibiting or eliminating the “wetness” insidethe shroud and on the surface of the valve/seal, the dosage form isdispensed without adhesion occurring between the dosage form and theshroud or valve/seal.

To protect the drug dosage forms from exposure to moisture either fromhumidity, saliva ingress, or accidental exposure to other water basedliquids, the dispensing device and the container or cartridge whichhouses the dosage forms within the device contains a desiccant.

Means for trapping or otherwise isolating saliva or moisture if itenters the device include, but are not limited to, a hydrophilic wickingmaterial or component, an absorbent or adsorbent material or component,a desiccant material or component, a separate track or channel formoisture to collect, a separate channel to communicate moisture to theabsorbents or adsorbents, or any combination of these materials orcomponents.

A desiccant is a sorbant, in the form of a solid, liquid, or gel thathas an affinity for water, and absorbs or adsorbs moisture from itssurrounding, thus controlling the moisture in the immediate environment.Any commercial desiccant may be used. Commercial desiccants typicallytake the form of pellets, canisters, packets, capsules, powders, solidmaterials, papers, boards, tablets, adhesive patches, and films, and canbe formed for specific applications, including injection moldableplastics. There are many types of solid desiccants, including silica gel(sodium silicate, which is a solid, not a gel), alumino-silicate,activated alumina, zeolite, molecular sieves, montmorillonite clay,calcium oxide and calcium sulfate, or others, any of which may be usedin the claimed dispensing devices. Different desiccants have differentaffinities to moisture or other substances, as well as differentcapacities, and rates of absorption or adsorption. Also, different typesof desiccants will come to equilibrium at different relative humiditiesin their immediate surroundings. As a means for protecting the dosageforms and the internal portions of the dispensing device from moisture,one or more desiccants may be employed at the proboscis; in or adjacentto the dosage form; In or adjacent the delivery pathway; in or adjacentthe dosage form, tablet magazine or cartridge; in or adjacent to othercomponents of the dispensing device; formed as an injection moldedcomponent of the dispensing device; a compressed desiccant that ispressed into location; or desiccant in any other location within orwithout the device.

In one preferred embodiment, the desiccant snaps into a cavity in theside of the cartridge. There are holes in the desiccant cavity thatconnect it to the dosage form stack, exposing the dosage forms todesiccant and keeping them dry.

The claimed dispensing devices rely on valves, pads, seals, the restposition of the push rod, proboscis design and a shroud to minimize oreliminate saliva ingress or moisture into the dispensing device duringadministration of the dosage form.

Valves for use in the claimed devices are typically dome/trocar typevalves that provide enough sealing force to keep saliva and/or moisturefrom entering the device and serve to minimize or eliminate salivaingress or moisture by dosing the distal orifice during dispensing andafter a dosage form has been dispensed.

Pads for use in the claimed devices have various geometries that aid incontacting or communicating with the pushrod in order to removed liquidfrom the push rod surface. Such pads typically contain hydrophilicproperties and serve to minimize or eliminate saliva ingress or moistureingress by transporting the liquid away from the track and push rod.

Seals and wipers for use in the claimed devices are designed to maintaina uniform seal around a drug dosage form and a pushrod during deliveryand are characterized by flexible materials that impart a seal aroundthe dosage form and pushrod and serve to minimize or eliminate salivaingress or moisture by sealing and wiping the orifice and pushrodbefore, during, and after dispensing.

The rest position of the push rod in the claimed devices ischaracterized by positioning the pushrod in an intermediate locationdistal to the cartridge exit, and proximal to the distal dispensingorifice and serves to minimize or eliminate saliva ingress and moistureby allowing the pushrod to reside in a location that contains adesiccant, absorbents, or channel that dries the pushrod while at restbetween dosage dispenses.

The proboscis design for use in the claimed devices is characterized bya distal device shape, typically an S-shape, that aids in use of thedevice and/or placement of the tip on the oral mucosa of the subject.The shape typically has curves, angles, and geometries such that itenables proper use of the device and placement of the dosage form on theoral mucosa of the subject, e.g., in the sublingual space.

The shroud of the claimed devices has a geometry that forms a barrierbetween the device and the oral mucosa and tongue, a relief for dosageform delivery, and an interior that is hydrophobic or hydrophilic andserves to minimize or eliminate saliva ingress or moisture ingress bycreating a barrier from the oral mucosa contacting the valve area anddosage form, aiding in dosage form dispensing and discouraging dosageform adherence to the shroud. The shroud may have a rounded interiorsurface or other geometries to mitigate the dosage form adhering to theshroud. The shroud limits the ability of the tongue or sublingual mucosato contact the dosage form dispensing area, thereby controlling salivacontact and ingress.

FIGS. 11A-E provide schematic depictions of a variety of aspects of oneembodiment of a drug dispensing device constructed to hold a pluralityof dosage forms for oral transmucosal delivery. FIG. 11A is a schematicdepiction of a fully assembled or single piece dispensing device 11 ofthe invention. In FIG. 11B, the dispensing device 11 includes a reusablehead 13 and a disposable body 15; in FIG. 11C the dispensing device 11further includes a cartridge 17 in FIG. 11D the dispensing device 11includes a valve 33, a proboscis 31, a latch button 19, a power traincoupling 25, a hub lock 21 and a dispense button 23; and FIG. 11E is aschematic depiction of a reassembled and complete dispensing device 11.

FIG. 12 provides a schematic depiction of an exemplary dispensing devicewherein the dispensing tip comprises a shroud 29 having a one or moreof: a wiping/sealing valve 37, an absorbent pad 39, a drug dryingchamber/moisture communication channel 43, desiccant in the channel 45,a cartridge 17 containing dosage forms 67 and desiccant in the cartridge47.

FIGS. 13A and 13B are schematic depictions of an exemplary geometry forthe dispensing tip that prevents contact of one or more seals 33, 35with the moist or wet surface of the oral mucosa via a shroud 29.

FIGS. 14A-D are a schematic depiction of an exemplary proboscis 31 of adispensing device 11 wherein the proboscis 31 comprises a shroud 29, avalve 33 for dispensing a dosage form 67 and a cut-out/relief 55 for thedosage form 67 to be placed against the oral mucosa and not moved whenthe device 11 is withdrawn following dispensing.

A means for minimizing saliva ingress and moisture into the claimeddevices is important for preservation of the integrity of dosage formsduring storage, e.g., prior to an between oral transmucosaladministrations.

The claimed dispensing devices may be used to administer a drug dosageform that is sensitive to moisture and/or humidity. In such cases, adrug dosage form cartridge serves to protect the drug dosage form fromliquid and vapor phase moisture, including humidity, liquid moisture,saliva, mucus, etc. The cartridge may be cylindrical, disk-shaped,helical, rectilinear, non-ordered, or may take the form of anyassemblage of drug dosage forms that allows the drug dispensing deviceto dispense them in a controlled manner. To prevent the unused drugdosage forms from absorbing moisture or otherwise becoming exposed tomoisture prior to use, the cartridge may provide a means of sealing thedrug dosage forms from exposure to moisture. This may accomplished byuse of a cartridge that contains individually packaged drug dosage formsseparated by a thin impermeable foil or impermeable material such thatwhen one drug dosage form is dispensed from the cartridge, the sealprotecting the remaining dosage forms remains unbroken. Alternatively,the dosage forms may be packaged in such a manner within the cartridgethat two or more dosage forms are packaged together in each separatesealed compartment. In some embodiments, all of the dosage forms in acartridge may be packaged together in a foil sealed compartment.

A drug cartridge that houses small volume drug dosage forms within thedispensing device may afford a seal against moisture by means of aseptum, an elastomeric seal or valve, a sliding, translating, hingeddoor or valve, or by means of sealing against another component of thedrug dispensing device when loaded. In this manner, a single re-sealableseal may be opened either independently or by means of the passage of adosage out of the cartridge. Once the dosage form is delivered from thecartridge, the re-sealable seal on the cartridge may be re-sealed toprevent moisture or other contaminants from damaging the remaining drugdosage forms within the cartridge. The cartridge may further have anon-re-sealable seal that is broken when it is loaded into the drugdispensing device or upon delivery of the first dosage form from thecartridge.

In other embodiments, the cartridge contains a desiccant or otherabsorbent or adsorbent material to absorb or adsorb moisture thatpenetrates the cartridge either prior to use or during normal use. Acartridge for use in a claimed dispensing device may contain anycombination of individually sealed dosage forms, multiply sealed dosageforms, re-sealable seals, non-re-sealable seals, desiccants, absorbents,or adsorbents. In one embodiment, a cartridge for use in the dispensingdevice in holds sufficient drug dosage forms for 1-5 days of treatment,e.g. 40 dosage forms or sufficient drug dosage forms to provide 48 to 72hours of treatment.

Pushrod Design

FIGS. 15A-D provide a series of flow diagrams for use of an exemplarydispensing device showing pusher logic, wherein FIG. 15A shows the LOADfeature; FIG. 15B shows the device calibration logic flow. Referring toFIG. 16, the pushrod 51 is advanced from position 65, picks up theshipping tablet 69 at position 63, and is further advanced to position61. At position 61, the device senses the presence of the shippingtablet 69 and/or push rod 51. In doing so, the device is calibrated andknows the location of the shipping tablet 69 and/or end of the push rod51 regardless of assembly tolerances, variations in push rod length andpush rod end conditions. Following this calibration, the push rod 51advances the shipping tablet 69 from position 61 to position 57 wherethe shipping tablet 69 is dispensed from the device. During thisoperation, the device is able to distinguish between a shipping tablet69, a push rod 51, and a drug dosage form 67. This differentiationenables the device to confirm that a cartridge is unused because ashipping tablets is the first thing dispensed from a new cartridgeduring device setup. The feature that provides the means fordifferentiating between the shipping tablet, push rod, and dosage form67 may be optical, physical, RF, electronic (resistive, capacitive, orother) or magnetic. The push rod 51 advance from position 65 andposition 57 described above, could be continuous or intermittent and aphysical stop at position 61 is not required. The push rod 51 thenretracts from position 57 to position 59, placing the device 11 in theready position with the push rod 51 under the remaining dosage forms 67.In this position, the push rod 51 keeps dosage forms 67 frominadvertently falling out of the device 11.

FIG. 15C shows the device dispense logic flow. referencing FIG. 16,following a dose command, the push rod 51 retracts from position 59 toposition 65, allowing the dosage forms 67 to advance into the push rodtrack. The push rod 51 then advances from position 65, picks up a dosageform at position 63, and then dispenses the dosage forms 67 from thedevice at position 57. Between positions 63 and 57, the presence of adosage form 67 is sensed/confirmed at position 61 by the positionsensor. The push rod then retracts from position 57 to position 59,placing it in the ready position with the push rod 51 is under theremaining dosage forms 67. In this position, the push rod 51 is allowedto dry before the next dosage form 67 dispense, as well as keeps dosageforms 67 from inadvertently falling out of the device 11.

FIG. 15D shows the device disassemble logic flow. Following a“disassemble” command, the push rod 51 is moved to position 65. Thisallows for the removal of any remaining dosage forms 67 without push rodinterference.

FIG. 16 is a schematic depiction of an exemplary dispensing deviceshowing the stages of push rod/dosage form interaction during deviceuse. In FIG. 16, the push rod 51, dosage forms 67, shipping tablet 69,spring 73 and position sensor 71 are shown. During use, the push rod 51moves between positions 57, 59, 61, 63 and 65, also shown in FIG. 16 andfurther detailed in FIGS. 15A-D.

Dosing History/Feedback

Further embodiments of the device include the ability to storehistorical use information and the ability to transmit such information.The device may be capable of unidirectional (downloading) orbidirectional information transfer. For example, an exchange ofinformation may be accomplished by downloading stored information to acomputer through a physically wired interface, such as a USB or anyother communication connection. Alternatively, information may becommunicated via a wireless system.

In another embodiment, the dispensing device has a dose counting featurethat monitors and stores the history of drug usage. Such information mayinclude historical use information, for example the number of dosagesstored and dispensed, and the times of dispensing.

Calibration

The dispensing device may be capable of self-calibration of the dispensemechanism, or the device may be calibrated manually. This process mayemploy a shipping tablet with a feature or features that physicallydifferentiate it from a drug dosage form or the push rod. These featuresmay be designed so that device calibration precision is higher that thatattainable using a dosage form or push rod. The differentiating featuremay be physical, optical, radio frequency (RF), electronic or magnetic.

Patient Identification Feature

In one aspect, the dispensing device comprises a detecting means forpatient identification such as a fingerprint reader, an optical retinalreader, a voice recognition system, a face recognition system, a dentalimprint recognition system, a visual recognition system, or a DNAreader. The dispensing device may employ one or more means to identifythe user, enabling the system to determine if a dispensing request isbeing made in an authorized or unauthorized manner. It is important foreffective delivery of many potential drugs and drug dosage forms toensure that the dispensing device is not accidentally or intentionallyused by an unauthorized individual to prevent accidental or intentionaldiversion of the drug. Such patient identification systems may recognizeone or more users, for example, in an inpatient hospital setting thedispensing device could be programmed to recognize the patient to whomit is prescribed, as well as authorized healthcare providers such asnurses and physicians. In an outpatient home setting, for example, thedispensing device may only respond to the patient to whom it isprescribed.

The dispensing device may employ any means of user identification,including fingerprint identification, RFID detection with the use of anactive or passive RFID tag on bracelet, necklace, clip, belt, strap,adhesive patch, implant, or means of locating and affixing a tag, retinaidentification, DNA identification, voice recognition, password or codeentry, physical key, electronic or magnetic key, personal area networkidentification using the human body or clothing as a data or signalconduit, optical scanner or face recognition, sonic, subsonic orultrasonic identification, or any other means of identifying anindividual and verifying their identity.

One method of patient identification is the use of a short distance(“near field”) passive RFID tag attached to a bracelet, necklace,adhesive patch, clothing tag, orally mounted device, like an orthodonticretainer, belt, strap, some combination of these, or another location.When an RFID tag is used in the “near field”, roughly defined as about16% of the wavelength of the received signal, the tag behaves in theinductive mode of operation, coupling between the reader and tag antennamagnetically. The near field is characterized by at least two features:first is a rapid decline in field strength with distance, and second isa strong directionality of the signal. In the near field, the signalstrength falls off very rapidly, with a signal strength loss ofapproximately 60 dB per decade in distance. For good inductive couplingbetween the transmitter antenna and the RFID tag antenna, the twoantennas are oriented in parallel planes with the axes through thecenter of each antenna in dose proximity. Strong signal strength (robustpatient identification) is provided when the device is very dose to theRFID tag. At the same time, a very poor signal is provided when thedevice is further away from the tag, which helps prevent unauthorizeduse by someone other than the patient who attempts to use the device. Itis preferable to operate in this near field region with good antennaalignment. Furthermore, it is preferable to operate with a very shortdistance of adequate signal strength for a positive identification, sothat it is very difficult to receive a signal if the device is not inthe proper orientation and proximity to the RFID tag. To attain a shortdistance and a proper alignment between antennas, the dispensing devicemay be designed so as to properly locate the RFID reader antenna,mounted in the dispensing device, adjacent to an RFID tag antenna,mounted, for example, on a wrist band or bracelet, or a clothing tag onthe collar, or an adhesive patch on the hand, arm, cheek, neck, orelsewhere. Furthermore, an RFID tag antenna on a wrist band or braceletmay be held in proper alignment and location by means of a smalladhesive patch that prevents the bracelet from moving or rotation on thewrist.

In another embodiment, the dispensing device employs a high frequencyRFID reader for use in the inpatient (hospital, clinic, etc.) setting,operating on or near the 13.56 MHz frequency band, and the patient is befitted with a matching RFID tag and antenna on a disposable bracelet orwrist band, designed in such a way that if the bracelet or wrist band isremoved the RFID tag, the antenna, or another component of theassociated circuit will be damaged or destroyed, rendering the braceletor wrist band non-functional. In one example, the range of the RFIDcommunication is short, between 0 inches and 10 inches preferably, morepreferably between 0 and 5 inches, and most preferably between 0 and 3inches, and may additionally be directional, allowing proper use by theintended patient to be easy and reliable, while at the same time makingunauthorized use by another individual difficult, very difficult, orimpossible.

Lock Out

The dispensing device provides for lock out, requiring the patient tocommunicate with the physician or other authorized care giver to unlockthe device for the next fixed period. In this way the device and dockprovide for safe drug administration due to greater physician oversightand care management.

The dispensing device provides a means for adjusting both the initialdose and subsequent doses, as well as the lock-out time. The initialdose and lock out time may subsequently be adjusted dependent uponpatient response, duration of treatment and the like.

The initial timed lock-out period for a claimed dispensing device istypically from about 1 minute to about 60 minutes, from 3 minutes to 40minutes or from 5 minutes to 30 minutes, and in particular cases is setat any one minute interval from 1 to 60 minutes, e.g., 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60 minutes.

In some cases, a dispensing device has a fixed lockout between doses andmay exhibit a shutdown after a fixed period of time. In other cases, thelock-out time is a programmable lock-out time. The lock-out time mayalso be a fixed time lock-out interval, a predetermined lock-outinterval, a predetermined variable lock-out interval, a lock-outinterval determined by an algorithm or a variable lock-out intervalcommunicated to the device from a remote computer or docking station.

Additional Features

A dispensing device may provide the ability to recognize a specificcartridge by a mechanical, optical (e.g. bar code), electronic (e.g.microchip), magnetic, radio frequency, chemical, or other means ofdetecting and identifying the cartridge. In one exemplary embodiment,the drug-containing cartridge contains a physical keying detail on thecartridge that is physically detected by a sensor or switch or a seriesof sensors or switches in the dispensing device. Furthermore, thedispensing device may communicate unidirectionally or bi-directionallywith the cartridge to exchange information. Such information may includedrug name, dosage strength, usage information, lockout period,manufacturing lot number, indications for use, side effects, druginteractions, date of manufacture, date of expiration, serial number,number of doses in the cartridge, or any other relevant information. Thedispensing device may be able to write, in addition to read, informationto the cartridge, like date used, nurse or patient identification,number of doses used, etc.

The dispensing device may provide mechanical protection for the dosageforms contained therein, preventing breakage, chipping, hydration etc.,thereby allowing for dispensing of the undamaged dosage forms containedtherein. This is of particular importance for small fragile and friabledosage forms.

The drug dispensing device may be powered by a battery, capacitor, fuelcell, or other power supply source, or may require no electrical power,but be manually activated.

In some embodiments, the dispensing device is capable of issuing alarmsor other notifications when functional or safety issues arise. The alarmor other notification may trigger an alert on the dispensing device, ona dock or other peripheral device; on a computer or by means of a wiredor wireless network, or may alert other remote devices. The alarm ornotification may be audible, tactile, visual, or may employ other meansof notifying one or more individuals.

Docking Station

In certain embodiments, the device includes a portable or fixed dockingstation that may query the device, reset it between dosing, lock it whennot properly accessed, and control the dosing regimen. The drugdispensing device may communicate with a physician or care giver, viathe dock, or by a wired or wireless communication means.

The dispensing device may employ one or more levels of interface fordifferent types of authorized users, for example the patient, the nurse,the physician, pharmacist or other authorized medical or healthcarepersonnel. These different interfaces may include components such askeypads, buttons, graphical icons and instructions, lights, LED's,monochrome or color graphical or text displays, touch-screens, LCD's,sounds, tactile feedback, voice recognition interfaces, and other inputand output devices and means. The activity, or mode, of the userinterface may be determined by the mode of operation of the dispensingdevice, by a login or access activity by a user such as a password orcode entry, by the connection or disconnection of the dispensing devicefrom a dock, computer, or network, or by the detection of an authorizedaccess key, such as a key, and/or RFID tag, or similar combination. Uponchanging the interface mode, the functionality of the device may bechanged, either activating, inactivating or changing the functionalityof the various interface components described above. By allowing thedevice to have one or more interface modes, with differing functionalityassociated with each one, the device can be optimized for various uses.

Base Station

In some embodiments the drug dispensing system includes a base stationfor recharging the drug dispensing device and the portable docking FOBbetween uses. This base station allows for recharging the batteries orfuel cells in multiple dispensing devices and/or FOBs simultaneously. Inaddition to recharging the drug dispensing devices and FOBs, the basestation may provide one or more of the following functionality: wirelessor wired connectivity to a peripheral device, computer or network;feedback on the charging state for the devices being recharges; aninterface for viewing, adding, deleting, or modifying the data on a drugdispensing device or FOB; a means for synchronizing data betweenmultiple drug dispensing devices and/or FOBs; and a means for conductinga diagnostic test on drug dispensing devices and/or FOBs.

IX. Methods and Systems for Delivering Small Volume Sufentanil DosageForms Using a Device

Methods and systems for delivering small volume sufentanil-containingdosage forms using a device are provided. FIG. 17 provides a schematicarchitecture connection diagram illustrating the various components thatmay be included in a dispensing device or system for dispensing smallvolume drug dosage forms, including a device with a separate head 13,body 15 and cartridge 17, a portable docking FOB 113, Patient RFID 115and a base station 117. A block diagram illustrating one aspect ofcommunication in a drug dispensing system, including an RFID tag, a drugdispensing device, a base station/dock and a healthcare providerpersonal computer system wherein a drug dispensing device cancommunicate with the physician or care giver, via the dock, or by meansof a wired or wireless communication method is provided in FIG. 18A.

A block diagram illustrating another aspect of communication in a drugdispensing system, including an RFID tag, a drug dispensing device, aportable docking FOB, a base station and a healthcare provider personalcomputer is provided in FIG. 18B. The drug dispensing device maycommunicate with the physician or care giver, via the FOB, by means of awired or wireless communication method to provide usage information andinformation regarding the respiratory status or blood pressure of thepatient to the physician at regular intervals. The FOB can be adapted toattach to a cord so as to allow the FOB to hang from the neck of thephysician or caregiver.

Exemplary features of the dispensing device include the following:

In one embodiment, the head, body, and cartridge comprise the handheldportion of the device. This device assembly has a latch to disconnectthe head and body, and a dispense button for patient use. The devicealso has lights to show lock-out status, errors, and power. In thisembodiment, the cartridge which contains the drug dosage forms and thebody are used a single time only.

The system may comprise a portable dock which is handheld, independentof the patient device and solely for healthcare professional use. Thedock enables higher level feature use such as deeper queries intopatient device use, the ability to upload device data, unlocking of thehead/body and the tether, lockout override for dosing the patient, and alarger reading display. The dock is also used to setup and take down thepatient device.

The system may also comprise an RFID bracelet that is activated via thedock and is worn by the patient to establish and control dosing tocorrect patient and to that patient alone. This feature prohibits use ofthe device by others.

The system may further comprise a recharging base used to charge thedock and heads and Is also used to update the heads and docks when newsoftware becomes available or when new users are programmed into thesystem.

The drug dosage forms are typically provided in disposable cartridgeswhich are loaded into the device prior to administration.

Exemplary set-up instructions for the device include the followingsteps:

The device head and dock are charged on the recharging station.

The device body and wristband are removed from the packaging.

The device head and dock are removed from the charging station.

The cartridge is loaded into the body by inserting a cartridge into thedevice body as indicated ensuring that the cartridge “clicks' and islocked in place.

The device body (with cartridge) is assembled onto the head.

The power button on the assembled device is pushed to power-up thesystem.

The power button on the dock is pushed to power-up the dock.

The assembled device is plugged into the dock.

A healthcare professional scans their fingerprint or inputs a uniquepassword in order to unlock the dock.

The device reads the label on the cartridge and the dock displays setupinformation, for example, the drug name, the quantity of tablets, thedrug concentration, the preset lockout time, the duration of use (72hours), and the battery status of the head.

After the information is read from the cartridge and displayed on thedock, the healthcare professional will be requested to confirm that allinformation is correct and will require a witness to verify theinformation.

The dock will require that the patient wristband be paired to the deviceby bringing the wristband dose to the device.

The device will read the band and request confirmation of the bandnumber; selection and confirmation of the number

The patient ID is entered into the dock. i.e. patient medical recordnumber

The wristband is placed on the patient's hand that will be used tooperate device.

Then, the dock will indicate that it is ready to dispense a plasticinitialization tablet or “shipping tablet”.

Upon confirmation, the device will dispense a plastic initializationtablet or “shipping tablet”. This step is used by the device tocalibrate the dispensing mechanism, initiate the cartridge for use, andallows the healthcare professional to verify proper use and to train thepatient with a “shipping” or placebo-type tablet.

Once the plastic initialization tablet or “shipping tablet” isdispensed, the dock will require the healthcare professional to confirmthat the plastic tablet was dispensed.

After confirmation, the display will indicate that the device is readyfor use.

In some cases, a tether can be connected to the device via the dock. Thedock will allow the healthcare professional to lock and unlock thetether as required.

If a patient will self administer a drug dosage form using the device,the patient will be trained prior to use.

Exemplary use of the claimed devices and systems is provided in Examples6-8.

The following examples are provided to illustrate the invention and arenot intended to limit any aspect of the Invention as set forth above orin the claims below.

EXAMPLES

The following examples are provided to illustrate the invention and arenot intended to limit any aspect of the invention as set forth above orin the claims below.

Two different sublingual sufentanil formulations were evaluatedincluding a slower-eroding form (erosion time of approximately 15-25minutes; Examples 1A and 18), and a faster-eroding form (approximateerosion time of 6-12 minutes; Examples 2A and 28). Patients were blockedwith a mu-opioid receptor antagonist, naltrexone (50 mg orally twice perday).

Sufentanil plasma concentrations with respect to time were analyzed andtabulated. The maximum sufentanil concentration in plasma (C_(max)),time to C_(max) (T_(max)) and terminal t_(1/2) were summarized for eachdose group. After the final dosing of the repeat-dose studies, thesufentanil t_(1/2) was determined. Comparisons were made between thearea under the curve (AUC) for each single administration of sublingualsufentanil dose vs. IV. C_(max), T_(max), and t_(1/2) data were comparedfor each sublingual sufentanil dosage vs. IV and sublingualadministration of sufentanil liquid.

Example 1 Evaluation of the Bioavailability and PharmacokineticsFollowing Sublingual Administration of a Small Volume Sufentanil DosageForm Example 1A

All subjects received a 10-minute IV infusion of 5 mcg sufentanil. Aftera 1-day washout period, each subject then received a single sublingualadministration of a dosage form (comprising a slow-eroding formulation)containing 2.5 mcg of sufentanil. On the two subsequent study days, thedose was escalated, and each subject received a dosage form (comprisinga slow-eroding formulation) containing 5 and 10 mcg of sufentanil.

Example 1B

All subjects received four repeated sublingual doses of a dosage form(comprising a slow-eroding formulation) containing 5 mcg of sufentaniladministered at 10-minute intervals.

The slow-eroding sublingual sufentanil formulation containing 10 mcgsufentanil is provided below:

Ingredient Amount Sufentanil Citrate 0.27% Mannitol (Pearlitol 200SD)73.77% PEG 8000 14.98% Polyox 303 3.00% Lutrol F68 2.00% Stearic Acid5.00% Mg Stearate 1.00% Total 100.00%

The sufentanil plasma concentration at various time points following asingle sublingual administration of a 2.5, 5, or 10 mcg sufentanildosage form (slow-eroding) or 4 administrations of a 5 mcg sufentanildosage form (slow-eroding) 10 minutes apart are shown in FIG. 1.

The mean sufentanil t_(1/2) was similar for all of the sufentanil dosesand varied from 1.56 hours (5 mcg sublingual dosage form) to 1.97 hours(10 mcg sublingual dosage form) with no obvious differences based ondose or route of administration (Table 1). The mean sufentanil C_(max)and AUC_(inf) increased with dose and were proportional to dose. TheT_(max) following a single sublingual administration of sufentanilranged from 0.68 to 0.77 hours. The bioavailability following sublingualadministration varied from 74.5% in subjects who were administered 5 mcgsufentanil dosage forms to 95.5% in subjects who were administered 10mcg sufentanil dosage forms.

Table 1 provides a summary of pharmacokinetic parameters includingC_(max), T_(max), AUC_(inf), F and t_(1/2). The C_(max) after multiplesublingual dosing was 46.36 pg/mL. The mean AUC_(inf) Increased withmultiple sublingual dosing of sufentanil and was generally proportionalto dose when compared to single sublingual administration. Thebioavailability of sufentanil following multiple sublingual dosing(97.2%) was greater than that following single administration at thesame dose level (74.5%).

TABLE 1 Summary of Sufentanil Pharmacokinetic Parameters Parameter 5 mcgIV 2.5 mcg 5 mcg 10 mcg 4 × 5 mcg C_(max) (pg/mL) 81.3 ± 28.1 6.8 ± 2.110.9 ± 3.5  27.5 ± 7.7  46.4 ± 12.4 T_(max) (hr) 0.16 ± 0.03 0.73 ± 0.130.77 ± 0.29 0.68 ± 0.22 1.16 ± 0.23 AUC_(inf) (hr*pg/mL) 38.4 ± 8.5 18.0 ± 4.5  27.4 ± 9.1  71.2 ± 20.7 146.5 ± 39.1  t_(1/2) (hr) 1.66 ±0.72 1.71 ± 0.51 1.56 ± 0.57 1.97 ± 0.85 3.29 ± 1.10 F (%) —  95.3 ±19.1*  74.5 ± 26.3*  95.5 ± 29.2*  97.2 ± 21.2* *% F calculated using 5mcg IV AUC

A paired t-test comparison of the mean sufentanil C_(max) and AUC_(inf)parameters was conducted after normalizing to the 10 mcg sublingualdose. The results are shown in Tables 2A and 28. Results show that theC_(max) and AUC_(inf) were dose proportional from 2.5 to 10 mcg.Supporting data for dose-proportionality of the C_(max) and AUC_(inf) isshown in FIGS. 2 and 3, respectively.

TABLE 2A Comparison of Sufentanil Pharmacokinetic Parameters Dose-Normalized to 10 mcg (2.5 mcg slow-eroding dosage forms) Differ-Standard t p n = 12 2.5 mcg 10 mcg ence deviation value value C_(max)(pg/mL) 27.24 27.45 −0.21 10.24 −0.07 0.946 AUC_(inf) 71.85 71.18 −0.6716.31 0.14 0.89 (hr*pg/mL)

TABLE 2B Comparison of Sufentanil Pharmacokinetic Parameters Dose-Normalized to 10 mcg 5 mcg slow-eroding dosage forms) Differ- Standard tp n = 12 5 mcg 10 mcg ence deviation value value C_(max) (pg/mL) 21.8127.45 −5.65 10.99 −1.78 0.10 AUC_(inf) 54.85 71.18 −16.33 17.94 −3.150.009** (hr*pg/mL) **p value < 0.05, statistically significant

Mean sufentanil plasma concentrations versus time (+/−SD) followingrepeated sublingual administration of 4×5 mcg sufentanil dosage forms(slow-eroding) at 10 minute intervals in healthy human volunteers ascompared to IV Infusion of 5 mcg sufentanil over 10 minutes are shown inFIG. 4.

A simulation was used to estimate sufentanil plasma concentrationfollowing administration of 4×5 mcg sublingual sufentanil dosage forms(slow-eroding), administered 10 minutes apart. The simulation wasconducted by superposition of the mean plasma concentration over timeprofile of a single administration of the 5 mcg sufentanil dosage form(slow-eroding). The simulation predicted and the observed mean (±SE)sufentanil plasma concentration versus time profiles were compared overa period of 12 hours (FIG. 5A) and a period of 2.5 hours (FIG. 5B). Thepredicted sufentanil concentrations based on the simulation closelytracks the observed sufentanil plasma concentration over time.

Example 2 Further Evaluation of the Bioavailability and Pharmacokineticsof Sufentanil Following Sublingual Administration of a Small VolumeDosage Form Example 2A

Subjects were administered 5 mcg of sufentanil solution via thesublingual route (N=2) or a 10-minute IV infusion of 5 mcg sufentanil(N=10), a single sublingual administration of a dosage form containing10 mcg of sufentanil (faster-eroding formulation) and four repeatedsublingual doses of a dosage form containing 10 mcg of sufentanil(faster-eroding formulation) administered at 20-minute intervals.

Example 2B

All subjects were administered a 20-minute IV infusion of 50 mcgsufentanil and a single sublingual administration of a dosage formcontaining 80 mcg of sufentanil (faster-eroding formulation).

The fast-eroding sublingual sufentanil formulation containing 10 mcgsufentanil is provided below:

Component Amount Sufentanil Citrate 0.26% Mannitol SD100 70.64%Di-Calcium Phosphate di-hydrate 20.00% HPMC K4M Premium CR 3.00% StearicAcid 5.00% Mg Stearate 1.00% BHT 0.10% Total 100.00%

The sufentanil plasma concentration (mean+/−SD) at various time pointsfollowing a single sublingual administration of 10 mcg and 80 mcgsufentanil dosage forms (faster-eroding) and 4 administrations of the 10mcg sufentanil dosage form (faster-eroding) 20 minutes apart are shownin FIG. 6.

The mean t_(1/2) was similar for the single sufentanil administrationsand varied from 1.72 hours (5 mcg IV) to 1.67 hours (10 mcg sublingual).The mean sufentanil AUC_(inf) increased with dose following single andmultiple sublingual sufentanil administrations. The bioavailability was60.9% in subjects treated with a single 10 mcg sublingual sufentanildosage form (fast-eroding) and 87.8% following multiple (4×10 mcg)sublingual sufentanil administrations.

A simulation was used to estimate sufentanil plasma concentrationfollowing administration of 4×10 mcg sublingual sufentanil dosage forms(faster-eroding), administered 20 minutes apart. The simulation wasconducted by superposition of the mean plasma concentration over timeprofile of a single administration of the 10 mcg sufentanil dosage form(faster-eroding). The simulation-predicted and the observed mean (±SE)sufentanil plasma concentration versus time profiles were compared overa period of 12 hours (FIG. 7A) and a period of 2.5 hours (FIG. 7B). Theobserved sufentanil plasma concentrations were greater than thepredicted sufentanil plasma concentrations (based on the simulation)over time.

TABLE 3 Summary of Sufentanil Pharmacokinetic Parameters Parameter 5 mcgIV 10 mcg 4 × 10 mcg 80 mcg 50 mcg IV C_(max) (pg/mL) 63.9 ± 28.2 16.5 ±6.8  78.7 ± 20.1 127.2 ± 42.3  561.1 ± 277.7 T_(max) (hr) 0.17 ± 0.0 0.84 ± 0.35 1.41 ± 0.25 0.89 ± 0.35 0.34 ± 0.11 AUC_(inf) (hr*pg/mL)39.4 ± 9.6  44.9 ± 24.6 253.4 ± 70.1  382.1 ± 88.2  528.0 ± 134.4t_(1/2) (hr) 1.72 ± 0.47 1.67 ± 0.67 3.54 ± 1.02 4.23 ± 0.90 3.69 ± 0.78F (%) —  60.9 ± 27.7*  87.8 ± 22.2*  70.1 ± 20.1* — *% F calculatedusing 5 mcg IV AUC

The bioavailability following sublingual administration of the 80 mcgsufentanil dosage form (faster-eroding) was 70.1%.

A paired t-test comparison of the mean sufentanil C_(max) and AUC_(inf)parameters was conducted after normalizing to the 10 mcg sublingualdose. The results presented in Table 4 show that the C_(max) andAUC_(inf) were dose proportional from 10 to 80 mcg. Supporting data fordose-proportionality of the C_(max) and AUC_(inf) is shown in FIGS. 8and 9, respectively.

TABLE 4 Comparison of Sufentanil Pharmacokinetic Parameters Dose-Normalized to 10 mcg (80 mcg faster-eroding dosage forms) Differ-Standard t p n = 11 10 mcg 80 mcg ence deviation value value C_(max)(pg/mL) 16.59 16.93 −0.34 8.04 −0.14 0.89 AUC_(inf) 45.02 50.88 −5.8623.85 −0.81 0.43 (hr*pg/mL)

A simulation of sufentanil concentrations following multipleadministrations of 10 or 15 mcg sublingual sufentanil dosage forms(slow-eroding), administered every 20 minutes was carried out. Dosageforms comprising the slow-eroding formulation resulted in abioavailability of greater than 95%, and therefore serve as a basis foran estimate of the highest predicted steady-state sufentanilconcentration following multiple administrations of 10 or 15 mcgsublingual sufentanil dosage forms. Steady-state sufentanilconcentrations can be reached in about 12 hours after repeatedsublingual doses at 20 minute intervals. The simulation predictedsteady-state sufentanil concentrations of 200 pg/mL for administrationof 10 mcg of sufentanil at 20 minute intervals and 300 pg/mL foradministration of 15 mcg of sufentanil at 20 minute intervals as shownin FIGS. 10A and 10B, respectively. The simulations suggest that aminimal re-dosing interval of 20 minutes is safe.

Example 3 Acute Pain Management in the Outpatient Setting byAdministering a Sufentanil-Containing Dosage Form Using a Device

A pharmacist loads a drug dispensing device with a drug cartridge whichincludes 40 sufentanil dosage forms. Each cartridge has two coloredinitialization tablets (called “shipping tablets”) arranged to be thefirst two tablets dispensed. The device has a means for loading thecartridge, which is either a port, hatch, or door that is secure andinaccessible to unauthorized users. Once the pharmacist has loaded thecartridge into the device, he locks the device access port, hatch ordoor. The pharmacist then docks the dispensing device for the first timeto a dock that is connected to a personal or other computer, using thedocking connector, and then programs the device. Programming involvesuploading the dosage strength of the dosage forms, the number of dosageforms loaded in the device, the prescribed frequency of dosage formusage, the number of dosage forms to be used per day, the current dateand time, the preferred language, a valid thumbprint or otheridentification for identifying the patient, and the physician'sidentification information, in case the device is lost and found.

Once the dispensing device is programmed, the pharmacist demonstratesproper usage and tests the device by dispensing a single shippingtablet. The pharmacist then gives the dispensing device to the patientand observes the patient dispense a shipping tablet to ensure properusage and functionality. Along with the dispensing device, thepharmacist provides the patient with a radio frequency identification(RFID) tag that must be within approximately 5 inches of the device toallow the dispensing device to operate.

When the patient wants to administer a dose of the drug, he or she willhold the dispensing device, and push any button to wake the device upfrom its sleep mode. The device will query the user for either athumbprint reading or a personal identification number (PIN). The devicewill then search for a validated RFID key within range. Once theseconditions are met, the dispensing device will query its internal memoryand dock to make sure that the dosage regimen programmed by thepharmacist is not being violated by the current usage request. At thispoint the device displays status information, such as the date and time,the number of doses left, the last time a dosage was used, the patient'sname, etc., and the pharmacist informs the patient that the device isready to dispense the dosage forms by a visual and/or audible signal.

The patient will hold the dispensing end of the device under his or hertongue and press the dispensing lever. When the dosage form is dispenseda tone will sound to inform the patient that the dosage form wasproperly delivered. At this point the device will lock down to preventfurther dispensing until the preprogrammed lock-out time has passed, atwhich time the device will be ready to use again.

Example 4 Acute Pain Management in the Inpatient Setting byAdministering a Sufentanil-Containing Dosage Form Using a Device

A post operative patient requires acute pain treatment followingsurgery. The surgeon prescribes oral transmucosal sufentanil to beadministered using the drug dispensing device. The attending nurse takesthe prescription order to the pharmacist or automated pharmaceuticalinventory management system (e.g. Pyxis) and obtains asufentanil-containing drug cartridge for sublingual delivery. Thecartridge is labeled and equipped with an RFID electronic tag containingdrug label information. The cartridge is labeled and equipped with anRFID electronic tag containing drug label information.

The nurse then takes a disposable dispensing portion of the drugdispensing device from inventory, and proceeds to a base station toobtain a reusable controller portion of the drug dispensing device thathas completed its recharge cycle and is ready for use. The nurse insertsthe drug cartridge into the disposable dispensing portion, and thenaffixes this to the reusable controller portion of the drug dispensingdevice and locks the disposable portion into the reusable portion of thedrug dispensing device. At this point the device reads the RFID tag onthe drug cartridge and uploads the appropriate drug information,including the type of drug, the dosage strength, the programmed lockoutperiod between doses, etc. The nurse confirms the proper drug cartridgeinformation has been read by the drug dispensing device and gives thedrug dispensing device to the patient for patient controlled dispensingof the pain medication.

When the patient requires pain medication, she takes the drug dispensingdevice in her hand, and places the dispensing tip in her mouth, underher tongue and presses the dispense button. The drug dispensing devicethen does an internal check to ensure that the proper lockout period haselapsed since the last dosage dispense. At this point the drugdispensing device dispenses a dosage form under the patient's tongue andprovides feedback that dosing was successful. The patient removes thedrug dispensing device from her mouth and allows the sublingual dosageform to dissolve under her tongue. The patient may attempt to dispenseas frequently as she desires, but the drug dispensing device will onlyallow successful dosing after the appropriate lockout period haselapsed. The drug dispensing device electronically logs the dispensingattempts and successful dispenses in its dosing history.

Periodically the nurse checks on the patient and drug dispensing device.During such checks, the nurse inspects the drug dispensing device to seethat there are no errors and to check the number of remaining dosageforms in the drug dispensing device, and returns it to the patient.

When the patient is discharged, the nurse takes the drug dispensingdevice and unlocks the reusable portion from the disposable portion,disposes of the cartridge and disposable portion of the drug dispensingdevice. The nurse then connects the reusable portion of the device to acomputer and uploads the patient use information from the drugdispensing device to the computer for input into the patient's medicalrecords. The nurse cleans the reusable controller portion and returns itto the base station for recharging.

Example 5 Acute Pain Management in the Inpatient Setting byAdministering a Sufentanil-Containing Dosage Form Using a Device and aPortable Dock

A post operative patient requires acute pain treatment followingsurgery. The surgeon prescribes oral transmucosal sufentanil to beadministered using the drug dispensing device. The attending nurse takesthe prescription order to the pharmacist or automated pharmaceuticalinventory management system (e.g. Pyxis) and obtains asufentanil-containing drug cartridge for sublingual delivery. Thecartridge is labeled and equipped with an RFID electronic tag containingdrug label information. The cartridge is labeled and equipped with anRFID electronic tag containing drug label information. The cartridgeincludes a shipping tablet or initialization tablet in the first to bedispensed location of the dosage form stack.

The nurse then takes a disposable dispensing portion of the drugdispensing device from inventory, and proceeds to a base station toobtain a reusable controller portion of the drug dispensing device thathas completed its recharge cycle and is ready for use. The nurse insertsthe drug cartridge into the disposable dispensing portion, and thenaffixes this to the reusable controller portion of the drug dispensingdevice. Next, the nurse takes a portable dock (or docking FOB) from thebase station where it has been recharging, and docks the assembled drugdispensing device to the portable dock. The portable dock and theassembled drug dispensing device communicate electronically and a setupmenu comes up on the portable dock for setting up the drug dispensingdevice.

At this point the device locks the reusable and disposable portionstogether, reads the RFID tag on the drug cartridge and uploads theappropriate drug information, including the type of drug, the dosagestrength, the lockout period between doses, etc. The dispensing devicewrites a code to the RFID tag on the cartridge identifying it as a usedcartridge. The nurse enters her fingerprint in the fingerprint reader onthe portable dock to gain secured access and proceeds to set up the drugdispensing device for use. The set up procedure includes enteringpatient identification, the nurse's identification, confirming theproper time on the device, and confirming the proper drug cartridgeinformation. The nurse then takes a disposable RFID bracelet and placesthis adjacent to the drug dispensing device at which point the drugdispensing device reads the tag and the nurse confirms that the properbracelet tag has been read.

The nurse then confirms proper setup of the drug dispensing device bypressing the dispensing button once. The drug dispensing deviceactuates, dispensing the shipping tablet facsimile into the nurses hand,confirming proper operation. The drug dispensing device detects thedispensing of the shipping tablet, allowing for an internal system checkof proper operation and internal calibration of the newly assembledsystem. If the internal dispensing check is successful, the portabledock queries the nurse to confirm that the shipping table was properlydispensed, and the nurse confirms the proper setup. The nurse thendisengages the drug dispensing device from the portable dock, andproceeds to the patient's bedside for the final steps of setup.

The nurse places the RFID bracelet on the patient's wrist and affixes atheft resistant tether to the patient's bed and the other end to thedrug dispensing device. The nurse then instructs the patient on properuse of the sublingual drug dispensing device, and gives the drugdispensing device to the patient for patient controlled dispensing ofsufentanil.

When the patient requires pain medication, she takes the drug dispensingdevice in her hand, and places the dispensing tip in her mouth, underher tongue and presses the dispensing button. The drug dispensing devicethen does an internal check to ensure that the proper lockout period haselapsed since the last dosage dispense, and that the patient's RFIDbracelet is present and readable. At this point the drug dispensingdevice dispenses a dosage form under the patient's tongue and provides afeedback that dosing was successful. The patient removes the drugdispensing device from her mouth and allows the sublingual dosage formto dissolve under her tongue. The patient may attempt to dispense asfrequently as she desires, but the drug dispensing device will onlyallow successful dosing after the appropriate lockout period haselapsed. The drug dispensing device electronically logs the dispensingattempts and successful dispenses in its dosing history.

Periodically the nurse checks on the patient and device. During such apatient check in the nurse brings a portable docking FOB and docks thedevice to the FOB. The electronic connection enables the nurse todownload the information from the drug dispensing device to the FOB.This information includes the use history, drug information, number ofremaining dosage forms and duration of use since initial set up. Thenurse then enters her fingerprint in the finger print scanner to gainaccess to the information and to drug dispensing device. Because thepatient is requiring an additional dose of drug prior to the lockoutperiod expiring, the nurse overrides the lockout period and then returnsthe drug dispensing device to the patient at which point the patient isable to take another dose.

The nurse leaves the patient's room with the portable docking FOB andreturns to the nurse's station to record the dosing history in thepatient's records. When finished the nurse returns the FOB to the basestation for recharging.

When the patient has used all of the dosage forms in the drug dispensingdevice, the nurse brings the portable docking FOB into the patient'sroom and docks the drug dispensing device to the FOB. The nurse thenenters her fingerprint in the fingerprint scanner on the FOB to gainsecured access to the drug dispensing device. Next, the nurse unlocksthe security tether and disconnects the drug dispensing device from thebed. She then unlocks the drug dispensing device and removes it from theFOB for disassembly. The nurse disconnects the disposable portion fromthe reusable portion, and removes the cartridge from the disposableportion. The nurse disposes of the disposable portion and the cartridge,and wipes the reusable controller portion with an antiseptic wipe toclean it before returning it to the base station. The reusablecontroller portion requires that the nurse return it to the base stationwhere it recharges and runs an internal diagnostic test before beingready for use again.

The nurse then proceeds to set up a new drug dispensing device asdescribed above and provides this to the patient.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practiced. Various aspects ofthe invention have been achieved by a series of experiments, some ofwhich are described by way of the following non-limiting examples.Therefore, the description and examples should not be construed aslimiting the scope of the invention, which is delineated by the appendeddescription of exemplary embodiments.

What is claimed is:
 1. A dosage form for oral transmucosaladministration to a subject, comprising: from about 2 micrograms toabout 200 micrograms sufentanil, wherein said dosage form is bioadhesiveand has a volume of less than 30 microliters or a mass of less than 30mg.
 2. The dosage form of claim 1, wherein the dosage form has a volumeof less than 10 microliters or a mass of less than 10 mg.
 3. The dosageform of claim 1, wherein after oral administration of the dosage form tothe subject, at least 50% of the drug delivery of sufentanil occurs viathe oral transmucosal route.
 4. The dosage form of claim 3, whereinafter oral administration of the dosage form to the subject, at least55% of the drug delivery of sufentanil occurs via the oral transmucosalroute.
 5. The dosage form of claim 3, wherein after oral administrationof the dosage form to the subject, at least 60% of the drug delivery ofsufentanil occurs via the oral transmucosal route.
 6. The dosage form ofclaim 1, wherein after oral administration of the dosage form to thesubject, the dosage form provides a Tmax of from about 19.8 minutes toabout 60 minutes.
 7. The dosage form of claim 1, wherein after oraladministration of the dosage form to the subject results in adose-normalized Cmax of about 2.72+/−0.84 pg/mL per mcg dosed.
 8. Thedosage form of claim 1, wherein after oral administration of the dosageform to the subject, the dosage form provides a Tmax of from about 19.8minutes to about 60 minutes and a dose-normalized Cmax of about2.72+/−0.84 pg/mL per mcg dosed.
 9. The dosage form of claim 8, whereinthe oral transmucosal administration is to the sublingual membrane. 10.The dosage form of claim 8, wherein the oral administration is to thebuccal membrane.
 11. The dosage form of claim 1, wherein after oraladministration of the dosage form to the subject, the dosage formprovides a Tmax with a coefficient of variation less than 40%.
 12. Thedosage form of claim 1, wherein a single oral transmucosaladministration of the dosage form to the subject results in abioavailability of greater than 65%.
 13. The dosage form of claim 1,wherein a single oral transmucosal administration of the dosage form tothe subject results in a bioavailability of greater than 75%.
 14. Thedosage form of claim 1, wherein a single oral transmucosaladministration of the dosage form to the subject results in abioavailability of greater than 80%.
 15. The dosage form of claim 1,wherein sufentanil is sufentanil citrate.
 16. A drug delivery devicecomprising the dosage form of claim
 1. 17. A dosage form for oraltransmucosal administration to a subject, comprising: a bioadhesivedosage form for delivery of sufentanil with a volume of less than 30microliters or a mass of less than 30 mg wherein the oral administrationof the dosage form to the subject results in a dose-normalized Cmax ofabout 2.72+/−0.84 pg/mL per mcg of sufentanil dosed.